Glycopeptide antibiotic derivatives

ABSTRACT

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity against a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of application Ser. No. 08/356,413, filed Dec. 15, 1994, abandoned, which is in turn a continuation-in-part of application Ser. No. 08/189,393, filed Jan. 28, 1994 and abandoned after the filing of application Ser. No. 08/356,413.

BACKGROUND OF THE INVENTION

New improved antibiotics are continually in demand, particularly for the treatment of human diseases. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties are some of the goals for improved antibiotics.

In the search for new antibiotics, structural modification of known antibiotics is attempted whenever possible. The glycopeptide antibiotics have such complex structures that even small changes are difficult. Furthermore, it is difficult to predict the effect these changes will make in the antimicrobial and physiological properties. Processes for modifying known antibiotics and the new active derivatives made by such processes, therefore, continue to be of great importance.

Previously, N-alkyl and N-acyl derivatives of the glycopeptides vancomycin, A51568A, A51568B, M43A and M43D have been prepared (U.S. Pat. Nos. 4,639,433, 4,643,987, and 4,698,327). Several of these compounds exhibited microbiological activity, including activity against vancomycin-resistant isolates. Nicas et al., Antimicrobial Agents and Chemotherapy, 33(9):1477-1481 (1989). In addition, European Patent Application Publication No. 0435503, published Jul. 3, 1993, describes certain N-alkyl and N-acyl derivatives of the A82846 glycopeptides, factors A, B, and C.

The formula I compounds of this invention are new members of the glycopeptide group of antibiotics. These new compounds are derivatives of known glycopeptide antibiotics that include vancomycin (U.S. Pat. No. 3,067,099); A82846A, A82846B, and 82846C (U.S. Pat. No. 5,312,738, European Patent Publication 56,071 A1); PA-42867 factors A, C, and D (U.S. Pat. No. 4,946,941 and European Patent Publication 231,111 A2); A83850 (U.S. Pat. No. 5,187,082); avoparcin (U.S. Pat. No. 3,338,786 and U.S. Pat. No. 4,322,343); actinoidin, also known as K288 (J. Antibiotics Series A 14:141 (1961); helevecardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 86/157,397); galacardin (Chem. Abstracts 110:17188 (1989) and Japanese Patent Application 89/221,320); and M47767 (European Patent Publication 339,982). The references listed above which describe these glycopeptides are incorporated herein by reference.

Enterococci are important human pathogens. Infections caused by enterococci are generally difficult to treat. Glycopeptides, such as vancomycin and teicoplanin, have become important therapies in the treatment of infections due to enterococci. However, strains of Enterococcus faecium and E. faecalis have recently been isolated that are resistant to vancomycin and teicoplanin. Leclercq et al., "Plasmid Mediated Resistance to Vancomycin and Teicoplanin in Enterococcus Faecium," The New England Journal of Medicine, 319(3):157-161 (1988), and Uttley et al., "Vancomycin-Resistant Enterococci," Lancet, 1:57-58 (1988). The isolates were also found to be resistant to other antibiotics. A recent survey found 7.9% of Enterococci in United States hospitals are now vancomycin resistant. "Nosocomial Enterococci Resistant to Vancomycin" Morbidity and Mortality Weekly Report 42 (30):597-598 (1993). In addition to their broad activity against gram-positive organisms, many of the glycopeptide compounds of this invention also exhibit improved antimicrobial activity against vancomycin-resistant isolates.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula I: ##STR1## or salt thereof, wherein: X and Y are each independently hydrogen or chloro;

R is hydrogen, 4-epi-vancosaminyl, actinosaminyl, ristosaminyl, or a group of the formula --R^(a) --R^(7a), wherein R^(a) is 4-epi-vancosaminyl, actinosaminyl, or ristosaminyl, and R^(7a), defined below, is attached to the amino group of R^(a) ;

R¹ is hydrogen, or mannose;

R² is --NH₂, --NHCH₃, --N(CH₃)₂, --NHR^(7b), or --N(CH₃)R^(7b), wherein R^(7b) is defined below;

R³ is --CH₂ CH(CH₃)₂, p--OH, m-Cl!phenyl, p-rhamnose-phenyl, p-rhamnose-galactose!phenyl, p-galactose-galactose!phenyl, or p-CH₃ O-rhamnose!phenyl;

R⁴ is --CH₂ (CO)NH₂, benzyl, p--OH!phenyl, or p--OH, m-Cl!phenyl;

R⁵ is hydrogen, or mannose;

R⁶ is 4-epi-vancosaminyl, L-acosaminyl, L-ristosaminyl, or L-actinosaminyl;

R⁷, as defined below, is attached to the amino group of R⁶ ; and

R⁷, R^(7a), and R^(7b) are each independently selected from the group consisting of hydrogen, (C₂ -C₁₆)alkenyl, (C₂ -C₁₂)alkynyl, (C₁ -C₁₂ alkyl)--R₈, (C₁ -C₁₂ alkyl)-halo, (C₂ -C₆ alkenyl)--R₈, (C₂ -C₆ alkynyl)--R₈, and (C₁ -C₁₂ alkyl)--O--R₈, provided that R⁷, R^(7a), and R^(7b) are not all hydrogen, and R⁸ is selected from the group consisting of:

a) multicyclic aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) hydroxy,

(ii) halo,

(iii) nitro,

(iv) (C₁ -C₆)alkyl,

(v) (C₁ -C₆)alkenyl,

(vi) (C₁ -C₆)alkynyl,

(vii) (C₁ -C₆)alkoxy,

(viii) halo-(C₁ -C₆)alkyl,

(ix) halo-(C₁ -C₆)alkoxy,

(x) carbo-(C₁ -C₆)alkoxy,

(xi) carbobenzyloxy,

(xii) carbobenzyloxy substituted with (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, halo, or nitro,

(xiii) a group of the formula --S(O)_(n') --R⁹, wherein n' is 0-2 and R⁹ is (C₁ -C₆)alkyl, phenyl, or phenyl substituted with (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, halo, or nitro, and

(xiv) a group of the formula --C(O)N(R¹⁰)₂ wherein each R¹⁰ substituent is independently hydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, phenyl, or phenyl substituted with (C₁ -C₆)-alkyl, (C₁ -C₆)-alkoxy, halo, or nitro;

b) heteroaryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) halo,

(ii) (C₁ -C₆)alkyl,

(iii) (C₁ -C₆)alkoxy,

(iv) halo-(C₁ -C₆)alkyl,

(v) halo-(C₁ -C₆)alkoxy,

(vi) phenyl,

(vii) thiophenyl,

(viii) phenyl substituted with halo, (C₁ -C₆)alkyl, (C₁ -C₆)alkenyl, (C₁ -C₆)alkynyl, (C₁ -C₆)alkoxy, or nitro,

(ix) carbo-(C₁ -C₆)alkoxy,

(x) carbobenzyloxy,

(xi) carbobenzyloxy substituted with (C¹ -C₆)alkyl, (C₁ -C₆) alkoxy, halo, or nitro,

(xii) a group of the formula --S(O)_(n') --R⁹, as defined above,

(xiii) a group of the formula --C(O)N(R¹⁰)₂ as defined above, and

(xiv) thienyl;

c) a group of the formula: ##STR2## wherein A¹ is --OC(A²)₂ --C(A²)₂ --O--, --O--C(A²)₂ --O--,--C(A²)₂ --O--, or --C(A²)₂ --C(A²)₂ --C(A²)₂ --C(A²)₂ --, and each A² substituent is independently selected from hydrogen, (C₁ -C₆)-alkyl, (C₁ -C₆)alkoxy, and (C₄ -C₁₀)cycloalkyl;

d) a group of the formula: ##STR3## wherein p is from 1 to 5; and R¹¹ is independently selected from the group consisting of:

(i) hydrogen,

(ii) nitro,

(iii) hydroxy,

(iv) halo,

(v) (C₁ -C₈)alkyl,

(vi) (C₁ -C₈)alkoxy,

(vii) (C₉ -C₁₂)alkyl,

(viii)(C₂ -C₉)alkynyl,

(ix) (C₉ -C₁₂)alkoxy,

(x) (C₁ -C₃)alkoxy substituted with (C₁ -C₃)alkoxy, hydroxy, halo(C₁ -C₃)alkoxy, or (C₁ -C₄)alkylthio,

(xi) (C₂ -C₅)alkenyloxy,

(xii) (C₁ -C₁₃)alkynyloxy

(xiii) halo-(C₁ -C₆)alkyl,

(xiv) halo-(C₁ -C₆)alkoxy,

(xv) (C₂ -C₆)alkylthio,

(xvi) (C₂ -C₁₀)alkanoyloxy,

(xvii) carboxy-(C₂ -C₄)alkenyl,

(xviii) (C₁ -C₃)alkylsulfonyloxy,

(xix) carboxy-(C₁ -C₃)alkyl,

(xx) N- di(C₁ -C₃)-alkyl!amino-(C₁ -C₃)alkoxy,

(xxi) cyano-(C₁ -C₆)alkoxy, and

(xxii) diphenyl-(C₁ -C₆)alkyl,

with the proviso that when R¹¹ is (C₁ -C₈)alkyl, (C₁ -C₈)alkoxy, or halo, p must be greater or equal to 2, or when R⁷ is (C₁ -C₃ alkyl)--R⁸ then R¹¹ is not hydrogen, (C₁ -C₈)alkyl, (C₁ -C₈)alkoxy, or halo;

e) a group of the formula: ##STR4## wherein q is 0 to 4; R¹² is independently selected from the group consisting of:

(i) halo,

(ii) nitro,

(iii) (C₁ -C₆)alkyl,

(iv) (C₁ -C₆)alkoxy,

(v) halo-(C_(l) -C₆)alkyl,

(vi) halo-(C₁ -C₆)alkoxy, and

(vii) hydroxy, and

(vii) (C₁ -C₆)thioalkyl;

r is 1 to 5; provided that the sum of q and r is no greater than 5;

Z is selected from the group consisting of:

(i) a single bond,

(ii) divalent (C₁ -C₆)alkyl unsubstituted or substituted with hydroxy, (C₁ -C₆)alkyl, or (C₁ -C₆)alkoxy,

(iii) divalent (C₂ -C₆)alkenyl,

(iv) divalent (C₂ -C₆)alkynyl, or

(v) a group of the formula --(C(R¹⁴)₂)_(s) --R¹⁵ -- or --R¹⁵ --(C(R¹⁴)₂)_(s) --, wherein s is 0-6; wherein each R¹⁴ substituent is independently selected from hydrogen, (C₁ -C₆)-alkyl, or (C₄ -C₁₀) cycloalkyl; and R¹⁵ is selected from --O--, --S--, --SO--, --SO₂ --, --SO₂ --O--, --C(O)--, --OC(O)--, --C(O)O--, --NH--, --N(C₁ -C₆ alkyl)--, and --C(O)NH--, --NHC(O)--, N═N;

R¹³ is independently selected from the group consisting of:

(i) (C₄ -C₁₀)heterocyclyl,

(ii) heteroaryl,

(iii) (C₄ -C₁₀)cycloalkyl unsubstituted or substituted with (C₁ -C₆)alkyl, or

(iv) phenyl unsubstituted or substituted with 1 to 5 substituents independently selected from: halo, hydroxy, nitro, (C₁ -C₁₀) alkyl, (C₁ -C₁₀)alkoxy, halo-(C₁ -C₃)alkoxy, halo-(C₁ -C₃)alkyl, (C₁ -C₃)alkoxyphenyl, phenyl, phenyl-(C₁ -C₃)alkyl, (C₁ -C₆)alkoxyphenyl, phenyl-(C₁ -C₃)alkynyl, and (C₁ -C₆)alkylphenyl;

f) (C₄ -C₁₀)cycloalkyl unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

(i) (C₁ -C₆)alkyl,

(ii) (C₁ -C₆)alkoxy,

(iii) (C₁ -C₆)alkenyl,

(iv) (C₁ -C₆)alkynyl,

(v) (C₄ -C₁₀)cycloalkyl,

(vi) phenyl,

(vii) phenylthio,

(viii) phenyl substituted by nitro, halo, (C₁ -C₆)alkanoyloxy, or carbocycloalkoxy, and

(ix) a group represented by the formula --Z--R¹³ wherein Z and R¹³ are as defined above; and

g) a group of the formula: ##STR5## wherein A³ and A⁴ are each independently selected from

(i) a bond,

(ii) --O--,

(iii) --S(O)_(t) --, wherein t is 0 to 2,

(iv) --C(R¹⁷)₂ --, wherein each R¹⁷ substituent is independently selected from hydrogen, (C₁ -C₆)alkyl, hydroxy, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, or both R¹⁷ substituents taken together are O,

(v) --N(R¹⁸)₂ --, wherein each R¹⁸ substituent is independently selected from hydrogen; (C₁ -C₆)alkyl; (C₁ -C₆)alkenyl; (C₁ -C₆)alkynyl; (C₄ -C₁₀)cycloalkyl; phenyl; phenyl substituted by nitro, halo, (C₁ -C₆)alkanoyloxy; or both R¹⁸ substituents taken together are (C₄ -C₁₀)cycloalkyl;

R¹⁶ is R¹² or R¹³ as defined above; and

u is 0-4.

Another aspect of the invention relates to compositions for the treatment of susceptible bacterial infections comprising a compound of formula I in combination with an acceptable pharmaceutical carrier. Methods for the treatment of susceptible bacterial infections with compositions of formula I are also a part of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The alkyl substituents recited herein denote substituted or unsubstituted, straight or branched chain hydrocarbons of the length specified. The term "alkenyl" refers to a substituted or unsubstituted, straight or branched alkenyl chain of the length specified. The term "alkynyl" refers to a substituted or unsubstituted, straight or branched alkynyl chain of the length specified.

The alkoxy substituents recited herein represent an alkyl group attached through an oxygen bridge. The term "alkenoxy" represents a alkenyl chain of the specified length attached to an oxygen atom.

The term "multicyclic aryl" means a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring; a stable, saturated or unsaturated, substituted or unsubstituted 12 to 14 membered organic fused tricyclic ring; or a stable, saturated or unsaturated, substituted or unsubstituted 14 to 16 membered organic fused tetracyclic ring. The bicyclic ring may have 0 to 4 substituents, the tricyclic ring may have 0 to 6 substituents, and the tetracyclic ring may have 0 to 8 substituents. Typical multi-cyclic aryls include fluorenyl, naphthyl, anthranyl, phenanthranyl, biphenylene and pyrenyl.

The term "heteroaryl", represents a stable, saturated or unsaturated, substituted or unsubstituted, 4 to 7 membered organic monocyclic ring having a hetero atom selected from S, O, and N; a stable, saturated or unsaturated, substituted or unsubstituted, 9 to 10 membered organic fused bicyclic ring having 1 to 2 hetero atoms selected from S, O, and N; or a stable, saturated or unsaturated, substituted or unsubstituted, 12 to 14 membered organic fused tricyclic ring having a hetero atom selected from S, O, and N. The nitrogen and sulfur atoms of these rings are optionally oxidized, and the nitrogen hetero atoms are optionally quarternized. The monocyclic ring may have 0 to 5 substituents. The bicyclic ring may have 0 to 7 substituents, and the tricyclic ring may have 0 to 9 substituents. Typical heteroaryls include quinolyl, piperidyl, thienyl, piperonyl, oxafluorenyl, pyridyl and benzothienyl and the like.

The term "(C₄ -C₁₀)cycloalkyl" embraces substituents having from four to ten carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl which may be unsubstituted or substituted with substituents such as alkyl and phenyl. This term also embraces C₅ to C₁₀ cycloalkenyl groups such as cyclopentenyl and cyclohexenyl. The term "(C₄ -C₁₀)cycloalkyl" also embraces bicyclic and tricyclic cycloalkyls such as bicyclopentyl, bicylohexyl, bicycloheptyl, and adamantyl.

The term "alkanoyloxy" represents an alkanoyl group attached through an oxygen bridge. These substituents may be substituted or unsubstituted, straight, or branched chains of the specified length.

The term "cyano-(C₁ -C₆)alkoxy" represents a substituted or unsubstituted, straight or branched alkoxy chain having from one to six carbon atoms with a cyano moiety attached to it.

The term "divalent (C₁ -C₆)alkyl" represents an unsubstituted or substituted, straight or branched divalent alkyl chain having from one to six carbon atoms. Typical divalent (C₁ -C₆)alkyl groups include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, neo-pentylene, and hexylene. Such divalent (C₁ -C₆)alkyl groups may be substituted with substituents such as alkyl, alkoxy, and hydroxy.

The term "divalent (C₂ -C₆)alkenyl" represents a straight or branched divalent alkenyl chain having from two to six carbon atoms. Typical divalent (C₂ -C₆)alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and the like.

The term "divalent (C₂ -C₆)alkynyl" represents a straight or branched divalent alkynyl chain having from two to six carbon atoms. Typical divalent (C₂ -C₆)alkynyl include ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene and the like.

The term "halo" represents chloro, fluoro, bromo or iodo.

The term "halo-(C₁ -C₆)alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C₁ -C₆)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl, and the like.

The term "halo-(C₁ -C₆)alkoxy" represents a straight or branched alkoxy chain having from one to six carbon atoms with from 0 to 3 halogen atoms attached to each carbon. Typical halo-(C₁ -C₆)alkoxy groups include chloromethoxy, 2-bromoethoxy, 1-chloroisopropoxy, 3-fluoropropoxy, 2,3-dibromobutoxy, 3-chloroisobutoxy, iodo-t-butoxy, trifluoromethoxy, and the like.

The term "heterocyclyl" embraces saturated groups having three to ten ring members and which heterocyclic ring contains a hetero atom selected from oxygen, sulfur and nitrogen, examples of which are piperazinyl, morpholino, piperdyl, methylpiperdyl, azetidinyl, and aziridinyl.

The invention includes salts of the compounds defined by formula I. Although generally neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, acetic acid, and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

The compounds of the present invention are prepared from compounds of the formula: ##STR6##

The compounds of formula II are defined in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     Formula II Compounds.sup.a                                                     antibiotic                                                                           R  R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                             R.sup.4                                                                               R.sup.5                                                                               R.sup.6                                                                           X Y                                       __________________________________________________________________________     vancomycin                                                                           H  van                                                                               H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A82846A                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H Cl                                      A82846B                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A82846C                                                                              4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H H                                       PA-42867-A                                                                           4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               H                                       PA-42867-C                                                                           4-epi                                                                             4-epi                                                                             H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  H H                                       PA-42867-D                                                                           4-epi                                                                             4-epi                                                                             H  N(CH.sub.3).sub.2                                                                   CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               H                                       A83850A                                                                              H  keto                                                                              H  N(CH.sub.3).sub.2                                                                   CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      A83850B                                                                              H  keto                                                                              H  NHCH.sub.3                                                                          CH.sub.2 CH(CH.sub.3).sub.2                                                           CH.sub.2 (CO)NH.sub.2                                                                 H  Cl                                                                               Cl                                      actinoidin                                                                           actin                                                                             acos                                                                              H  NH.sub.2                                                                            p-OH,m-Cl-                                                                            benzyl man                                                                               Cl                                                                               H                                                           phenyl                                                     avoparcin                                                                            risto                                                                             risto                                                                             man                                                                               N(CH.sub.3).sub.2                                                                   p-rha- p-OH-  H  H H                                                           phenyl phenyl                                              galacardin                                                                           risto                                                                             risto                                                                             man                                                                               NHCH.sub.3                                                                          p-gal-gal-                                                                            p-OH-  H  Cl                                                                               H                                                           phenyl phenyl                                              heleve-                                                                              risto                                                                             risto                                                                             H or                                                                              NHCH.sub.3                                                                          p-CH.sub.3 O-rha-                                                                     p-OH,m-Cl-                                                                            H  Cl                                                                               H                                       cardin      man     phenyl phenyl                                              M47767                                                                               actin                                                                             acos                                                                              H  NHCH.sub.3                                                                          p-OH,m-Cl-                                                                            benzyl man                                                                               Cl                                                                               H                                                           phenyl                                                     __________________________________________________________________________      .sup.a Abbreviations for the formula II compounds are: actin =                 actinosaminyl; acos = acosaminyl; 4epi = 4epi-vancosaminyl; gal =              galactosyl; keto = 4keto-vancosaminyl; man = mannose; rha = rhamnosyl;         rhagal = rhamnosylgalactosyl; risto = ristosaminyl; van = vancosaminyl.  

In a preferred embodiment of the invention, the formula I compounds are prepared from the A82846 antibiotics (A82846A, A82846B, and A82846C) and PA-42867-A. In a more preferred embodiment, the compounds of the present invention are prepared from A82846B ("A82846B derivatives"). A82846B is represented by formula I compounds wherein R is 4-epi-vancosaminyl, R¹ is hydrogen, R² is NHCH₃, R³ is CH₂ CH(CH₃)₂, R⁴ is CH₂ (CO)NH₂, R⁵ is hydrogen, R⁶ is 4-epi-vancosaminyl and X and Y are Cl. A82846B derivatives of the present invention having substituents at position R⁷ of formula I are list herein in the manner "R⁷ -A82846B". For example, the compound "phenylbenzyl-A82846B" has a phenylbenzyl substituent at position R⁷ in formula I.

Preferred formula I compounds include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is an unsubstituted multicyclic aryl. Of this group, naphthylmethyl-A82846B, acenapthlenyl-methyl-A82846B, and fluorenylmethyl-A82846B are more preferred.

Preferred formula I compounds also include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)-R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is an unsubstituted heteroaryl or a heteroaryl substituted by halophenyl. Of this group, 1-oxa!fluorenylmethyl-A82846B, chlorophenylbenzoxazolemethyl-A82846B, and phenylthienylmethyl-A82846B are more preferred.

Further preferred compounds of formula I include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is a group of the formula: ##STR7## wherein p is 1 and R¹¹ is selected from (C₂ -C₅)alkenyloxy, halo-(C₁ -C₆)alkoxy, (C₂ -C₁₀)alkanoyloxy, (C₁ -C₃)alkoxy substituted with (C₁ -C₄)alkylthio, and diphenyl-(C₁ -C₆)alkyl. Of this group, trifluromethoxybenzyl-A82846B, diphenylmethylbenzyl-A82846B, thiopropylethoxybenzyl-A82846B, acetoxybenzyl-A82846B, nonanoyloxybenzyl-A82846B, and tetrafluoroethoxybenzyl-A82846B are more preferred.

Still further preferred compounds of formula I include those A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is a group of the formula: ##STR8## wherein q is 1 to 5; r is 1; Z is selected from a single bond, divalent (C₁ -C₆)alkyl, divalent (C₂ -C₆)alkenyl, and --R¹⁵ --(C(R¹⁴)₂)_(s) --, wherein R¹⁵ is selected from --O--, --S--, --SO₂ --, and --OC(O)--, each R¹⁴ substituent is hydrogen, and s is 0 or 1; and R¹³ is selected from: (C₄ -C₁₀)cycloalkyl; phenyl; and phenyl substituted by nitro, halo, (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy, or halo(C₁ -C₃)alkyl. Of this group, chlorophenylbenzyl-A82846B, phenylbenzyl-A82846B, benzylbenzyl-A82846B, methylphenylbenzyl-A82846B, pentylphenylbenzyl-A82846B, methoxyphenylbenzyl-A82846B, pentoxyphenylbenzyl-A82846B, nitrophenoxybenzyl-A82846B, fluorophenylbenzyl-A82846B, phenylethynylbenzyl-A82846B, phenoxybenzyl-A82846B, benzyloxybenzyl-A82846B, nitrophenylbenzyl-A82846B, chlorophenoxybenzyl-A82846B, chlorobenzyloxybenzyl-A82846B, butylphenoxybenzyl-A82846B, trifluoromethylphenoxybenzyl-A82846B, dichlorophenoxybenzyl-A82846B, nitrobenzyloxybenzyl-A82846B, benzoyloxybenzyl-A82846B, cyclohexyloxybenzyl-A82846B, cyclohexanoyloxybenzyl-A82846B, thiophenylbenzyl-A82846B, chlorophenylsulfonylbenzyl-A82846B, and cyclohexylbenzyl-A82846B, cyclohexylethoxybenzyl-A82846B chlorophenoxynitro-benzyl-A82846B benzylmethoxybenzyl-A82846B, chlorophenoxynitro-benzyl-A82846B, and phenoxymethoxybenzyl-A82846B, benzoyloxy-dimethoxybenzyl-A82846B, cyclohexanoyloxy-dimethylbenzyl-AG2846B, trifluoromethylphenylbenzyl-A82846B, butylphenylthiobenzyl-A82846B, and bromophenylbenzyl-A82846B more preferred.

Still further preferred compounds of formula I include A82846B derivatives wherein R⁷ is --(C₁ -C₁₂ -alkyl)--R⁸, with --CH₃ --R⁸ being more preferred, and R⁸ is (C₄ -C₁₀)cycloalkyl substituted with (C₄ -C₁₀)cycloalkyl. Of this group of compounds, more preferred is cyclohexyl-cyclohexylmethyl-A82846B and butyl-cyclohexylmethyl-A82846B.

Formula I compounds that are prepared from A83850A or A83850B can be prepared from the reduced forms of these compounds. The reduced forms of compounds A83850A or A83850B are produced according to the method described in U.S. Pat. No. 5,187,082, which is incorporated herein by reference.

The compounds of this invention are prepared by reacting a formula II compound with an aldehyde to form an intermediate Schiff's base, which is subsequently reduced with a metal borohydride to give the desired N-alkyl amine.

In the first method of making the compounds of this invention, hereinafter Method A (described in Examples 1 and 2), the reaction for the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in a polar solvent, such as dimethylformamide (DMF) or methanol (MeOH), or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25° C. to about 100° C. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. for 30 minutes to 2 hours in a mixture of dimethylformamide and methanol, or in methanol. The intermediate Schiff's base is then reduced, preferably without isolation, to produce the corresponding N-alkyl derivative(s). The reduction of the Schiff's base can be effected using a chemical reducing agent such as a metal borohydride, for example, sodium borohydride or sodium cyanoborohydride. The reduction reaction can be carried out in a polar organic solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol. The reduction reaction can be carried out at a temperature of about 25° C. to about 100° C. for 1 to 5 hours. The reduction reaction is preferably carried out using an excess of sodium cyanoborohydride in a mixture of dimethylformamide and methanol or in methanol at about 60° C. to about 70° C. for 1 to 2 hours. Method A is preferable for benzylic aldehydes.

In a second method of making compounds of this invention, hereinafter Method B (described in Example 3), the formation of the Schiff's base is carried out under an inert atmosphere, such as nitrogen or argon, in the presence of the reducing agent, sodium cyanoborohydride, in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, at a temperature of about 25° C. to about 100° C. for 1 to 5 hours. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. for 1 to 2 hours in a mixture of dimethylformamide and methanol. Method B is preferable for non-benzylic aldehydes.

In a third method of making compounds of this invention, hereinafter Method C (described in Example 4), the formation of the Schiff's base is carried out a) under an inert atmosphere, such as nitrogen or argon, b) in the presence of the reducing agent, such as a metal borohydride, with sodium cyanoborohydride being most preferred, or a homogenous or heterogeneous catalytic hydrogenation agent(s), such as Crabtree's catalyst, Wilkinson's catalyst, palladium on carbon, platinum on carbon, or rhodium on carbon, c) in a polar solvent, such as dimethylformamide, methanol, or a mixture of polar solvents, such as a mixture of dimethylformamide and methanol, and d) at a temperature of about 25° C. to about 100° C. The reaction is preferably carried out at a temperature from about 60° C. to about 70° C. in methanol. The reaction is allowed to continue for about 20 to about 28 hours, at which time the reaction mixture is adjusted to about pH 7.5 to about pH 10, with a pH of about 9.0 being preferred. The pH adjustment halts the reaction. Because the product is marginally soluble in polar solvents, the solvent of the reaction can be exchanged to an alcohol such as ethanol, butanol, or isopropanol, with isopropanol being preferred, to allow for precipitation of the product. Method C is a preferred method of this invention in view of the increased product yield provided by this method. Another advantage of this reaction scheme is the increased ratio of preferred product (products substituted at the amino group of the sugar denoted as R¹ in Formula II compounds) to other products (products that are substituted at the amino groups of substitutents denoted as R and/or R³ of the Formula II compounds). By allowing the reaction to proceed for an extended period of time, such as 20 to 28 hours, products that are monosubstituted at positions denoted as R and R³ in the Formula II compounds are converted to disubstituted forms, making the preferred monosubstituted derivative easier to isolate.

The products of the reaction, obtained from either Method A, B, or C can be purified by preparative reverse-phase HPLC utilizing Waters C₁₈ Nova-Pak columns with ultraviolet light (UV; 235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minutes to 20% aqueous buffer/80% CH₃ CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

HPLC analysis of the reaction mixtures and final purified products can be accomplished utilizing a Waters C₁₈ MicroBonda-Pak column (typically 3.9×300 mm steel) or Waters Nova-pak C₁₈ RCM column (8×100 mm) with UV (235 nm or 280 nm) detection. A 30 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minute to 20% aqueous buffer/80% CH₃ CN at time=30 minutes is typically used, where the aqueous buffer is either TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid) or TFA (0.1% trifluoroacetic acid overall concentration).

The ratio of the aldehyde to the formula II compound and the reaction conditions determines the products of the reaction. The monosubstituted derivatives are those derivatives where a hydrogen atom of the amino group at position R¹ in formula II is replaced by one of the substituents listed above for formula I. When using Methods A or B, described above, the formation of monosubstituted derivatives substituted at the amino group of the amino sugar at position R¹ in the formula II compounds is favored by using a slight excess of aldehyde, a shorter reaction time, and a lower temperature. As noted above, Method C favors the formation of the monosubstituted derivative. The monosubstituted derivative is preferred. A large excess of the aldehyde favors the formation of disubstituted and trisubstituted derivatives of the formula II compounds. The disubstituted derivatives are the derivatives where a hydrogen atom at two of the locations selected from the amino group at position R³, and the amino group of the amino sugars designated as R or R¹ in formula II, are replaced by the reduced aldehyde moiety. The trisubstituted derivatives are the derivatives where a hydrogen atom at three of the locations selected from the amino group at position R³, and the amino group of the amino sugars designated as R or R¹ in formula II, are replaced by the reduced aldehyde moiety.

A further object of this invention are those compounds that are monosubstituted at the amino group of the amino sugar at position R of formula II, when such an amino sugar is present at this position, or at the amino group at position R³ of formula II. Further, the disubstituted and trisubstituted derivatives referred to above are also objects of this invention. These derivatives are useful in the treatment of bacterial infections. Methods A, B, and C (described above, and in the Examples) can be used to produce the monosubstituted, disubstituted and trisubstituted derivatives.

Preferably, Method D, described in Example 5, is used to produce those derivatives that are monosubstituted at the amino group at position R³ of formula II. Method D is also preferred for the synthesis of disubstituted derivatives substituted at the amino group of the amino sugar designated as R¹ in the formula II compounds, and at the amino group at position R³ in the formula II compounds.

Preferably, Method E, as described in Example 5, is used to produce those disubstituted derivatives that are substituted at the amino groups of the amino sugars designated as R¹ and R in the formula II compounds. Method E is also preferably used to produce the trisubstituted derivatives. The trisubstituted compounds can be formed when there is an amino sugar at the position designated as R in the formula II compounds.

Examples of compounds that have been prepared and are illustrative of the formula I compounds are listed in Tables 2A, 2B, and 2C. Table 2A lists compounds prepared by reacting an aldehyde with the glycopeptide A82846B. Table 2A lists the sidechain substitutions on the amino group of the 4-epi-vancosaminyl sugar of the 4-epi-vancosaminyl-O-glycosyl disaccharide of the A82846B compound. All of the compounds listed are monosubstituted derivatives.

Table 2B lists those compounds that were prepared by reacting an aldehyde with a variety of glycopeptide antibiotics other than A82846B. The compounds of Table 2B are monosubstituted at the amino group of the amino sugar designated as R¹ in formula II with the sidechain listed. All of the compounds listed are monosubstituted derivatives.

Table 2C lists exemplary compounds prepared by reacting an aldehyde with the glycopeptide A82846B. The compounds listed in Table 2C are substituted with the sidechain listed at the postions listed. The substituent positions listed are those referred to in formula II.

                  TABLE 2A                                                         ______________________________________                                         COMPOUND NO.                                                                              SIDECHAIN                                                           ______________________________________                                          1         2-naphthylmethyl                                                     2         4-phenylbenzyl                                                       3         1-naphthylmethyl                                                     4         4-phenoxybenzyl                                                      5         4-benzyloxybenzyl                                                    6         4-trifluoromethoxybenzyl                                             7         4-allyloxylbenzyl                                                    8         4-nonyloxybenzyl                                                     9         2-methoxy-1-naphthylmethyl                                           10        4-dodecyloxybenzyl                                                   11        9-phenanthranylmethyl                                                12        4-decyloxybenzyl                                                     13        9-anthranylmethyl                                                    14        4- phenylethynyl!4-phenylbenzyl                                      15        4-methoxy-1-naphthylmethyl                                           16        1-pyrenylmethyl                                                      17        9- 10-methyl!anthranylmethyl                                         18        9- 10-chloro!anthranylmethyl                                         19        2-benzthienylmethyl                                                  20        4- 4-hydroxyphenyl!benzyl                                            21        4- 4-octylphenyl!benzyl                                              22        4- 4-pentylphenyl!benzyl                                             23        4- 4-octyloxyphenyl!benzyl                                           24        3-pyridylmethyl                                                      25        5-nitro-1-naphthylmethyl                                             26        4-pyridylmethyl                                                      27        4-quinolylmethyl                                                     28        3-quinolylmethyl                                                     29        4-stilbenzyl                                                         30        2-quinolylmethyl                                                     31        2-pyridylmethyl                                                      32        2-fluorenylmethyl                                                    33        4-phenoxyphenethyl                                                   34        4- 4-pentylcyclohexyl!benzyl                                         35        4-benzylphenethyl                                                    36        4- 4-biphenyl!benzyl                                                 37        4-trifluoromethylbenzyl                                              38        trans-cinnamyl                                                       39        4- 1-oxa!fluorenylmethyl                                             40        4- 4-pentoxyphenyl!benzyl                                            41        4-thiomethylbenzyl                                                   42        2,3- 2-methyl-3- 4-t-butylphenyl!!propenyl                           43        9-(1-methyl)-acridinylmethyl                                         44        2-hydroxy-1-naphthylmethyl                                           45        4- 2-phenyl-6-methoxy!quinoylmethyl                                  46        4-diphenylmethylbenzyl                                               47        3,4 cyclohexenylmethyl                                               48        3,4-methylenedioxylbenzyl                                            49        3-phenoxybenzyl                                                      50        4-benzylbenzyl                                                       51        3-benzyloxy-6-methoxy benzyl                                         52        4-benzyloxy-3-methoxybenzyl                                          53        3,4-dibenzyloxybenzyl                                                54        4- 4-methoxyphenyl!benzyl                                            55        4- 3-cyanopropoxy!benzyl                                             56        3,4-ethylenedioxybenzyl                                              57        4- 4-nitrophenoxy!benzyl                                             58        2,3-methylenedioxybenzyl                                             59        2-benzyloxyphenethyl                                                 60        2-ethoxy-1-naphthylmethyl                                            61        2-benzylfurylmethyl                                                  62        3-phenoxyphenethyl                                                   63        4-phenoxyphenethyl                                                   64        4- 4-nitrophenyl!benzyl                                              65        6-methoxy-2-naphthylmethyl                                           66        3-methyl-5-thienylmethyl                                             67        5-phenyl-2-thienylmethyl                                             68        4-benzyloxyphenethyl                                                 69        3-benzyloxyphenethyl                                                 70        4- 2-nitrophenoxy!benzyl                                             71        5- 4-methoxyphenyl!-2-thienylmethyl                                  72        4-difluormethoxybenzyl                                               73        2,3,4,5,6-pentamethylbenzyl                                          74        5-iodo-2-thienylmethyl                                               75        4- 2- 2-chloroethoxy!ethoxy!benzyl                                   76        3,4-dimethylbenzyl                                                   77        3-acetoxybenzyl                                                      78        4-nitrobenzyl                                                        79        4-phenylethynylbenzyl                                                80        4- 2-chloro-6-fluorobenzyloxy!benzyl                                 81        4- 3,4-dichlorophenoxy!benzyl                                        82        5- 2,3-dihydrobenzfuryl!methyl                                       83        4- 2-(N,N-diethylamino)ethoxy!benzyl                                 84        2-bicyclo 2.1.2!heptylmethyl                                         85        2-hydroxy-5-phenylbenzyl                                             86        3- 4-chlorophenoxy!benzyl                                            87        4- 3-chlorophenoxy!-3-nitrobenzyl                                    88        4- 2-chlorophenoxy!-3-nitrobenzyl                                    89        3,5-dimethylbenzyl                                                   90        4- 4-ethylphenyl!benzyl                                              91        3-phenylbenzyl                                                       92        4- 3-fluorophenyl!benzyl                                             93        4- 4-chlorobenzyloxy!benzyl                                          94        4- 4-chlorophenoxy!-3-nitrobenzyl                                    95        4- 4-methylphenoxy!benzyl                                            96        4- 4-t-butylphenoxy!benzyl                                           97        4- 4-methylphenyl!benzyl                                             98        4- 4-methoxyphenoxy!benzyl                                           99        4-acetoxy-3-methoxybenzyl                                           100        4- (2-phenyl)ethyl!benzyl                                           101        3- 5-phenyl!pyridinylmethyl                                         102        4- 2-nitrophenyl!benzyl                                             103        2- 1-hydroxy!fluorenylmethyl                                        104        4-benzyl-3-methoxybenzyl                                            105        4- cyclohexylmethoxy!-3-ethoxybenzyl                                106        3- 3,3-dichlorophenoxy!benzyl                                       107        4- 4-propylphenyl!benzyl                                            108        4-thiophenylbenzyl                                                  109        4- alpha-hydroxybenzyl!benzyl                                       110        2, 2-dinitro-4-thiophenebenzyl                                      111        3- 3-trifluoromethylphenoxy!benzyl                                  112        4- t-butylethynyl!benzyl                                            113        4-phenoxy-3-methoxy-benzyl                                          114        4- 3-trifluoromethylphenoxy!-3-nitrobenzyl                          115        2-phenylthiobenzyl                                                  116        2- 4-chlorophenyl!-6-benzoxazoiemethyl                              117        4- alpha-methoxybenzyl!benzyl                                       118        4-cyclohexylbenzyl                                                  119        3- 3,4-dichlorophenoxy!benzyl                                       120        acenaphthienylmethyl                                                121        4- 1,1,2,2-tetrafluoroethoxy!benzyl                                 122        4-benzoyloxy-3,3-dimethoxybenzyl                                    123        3- cyclohexylmethoxy!benzyl                                         124        4-cyclohexyloxybenzyl                                               125        3- 2-quinoylmethoxy!benzyl                                          126        4- alpha-ethoxybenzyl!benzyl                                        127        4- cyclohexylethoxy!benzyl                                          128        4- alpha-propoxybenzyl!benzyl                                       129        4- 4-methyl-1-piperidino!benzyl                                     130        2-thiophene-1,2-cyclohexenylmethyl                                  131        4- 4-nitrobenzyloxy!benzyl                                          132        3- 4-trifluoromethylphenoxy!benzyl                                  133        3-benzoyl-2,4-dichlorobenzyl                                        134        4- 2-(2-thiopropyl)ethoxy!benzyl                                    135        4- 2-methyl-1-piperidino!benzyl                                     136        4-hydroxybenzyl                                                     137        4- 2-pyridyl!benzyl                                                 138        4-acetoxybenzyl                                                     139        5,6-benzonorbornylmethyl                                            140        3-phenylcyclopentylmethyl                                           141        1-adamantylmethyl                                                   142        3- cyclohexylmethoxy!-4-methoxybenzyl                               143        2- 2-glucosyl!benzyl                                                144        4- 4-pentoxybiphenyl!benzyl                                         145        3,4-dihydroxybenzyl                                                 146        4- 4-methylpiperazino!benzyl                                        147        4-morpholinobenzyl                                                  148        4- 4-chlorophenylsulfonyl!benzyl                                    149        4-methylsulfonyloxybenzyl                                           150        4-benzoyloxybenzyl                                                  151        5-phenyl-3-pyridinylmethyl                                          152        4- N,N-bis(2-chloroethyl)amino!benzyl                               153        3-cyclohexyloxybenzyl                                               154        4- 2-t-butoxyethoxy!benzyl                                          155        3,3-dichloro-4-hydroxy-benzyl                                       156        1,2,3,4,-tetrahydro-9-anthranylmethyl                               157        4-cyclohexanoyloxybenzyl                                            158        4-nonanoyloxybenzyl                                                 159        4- phenylsulfinyl!benzyl                                            160        4-anilinobenzyl                                                     161        cyclohexylmethyl                                                    162        3-benzoyloxybenzyl                                                  163        3-nonanoyloxybenzyl                                                 164        4- cyclohexyl!cyclohexylmethyl                                      165        3-cyclohexanoyloxybenzyl                                            166        4- cyclohexanoyloxy!-3,3- dimethoxy!benzyl                          167        4- nonanoyloxy!-3,3- dimethoxy!benzyl                               168        1,2,3,4-tetrahydro-6-naphthylmethyl                                 169        2-hydroxybenzyl                                                     170         2- 6,6-dimethyl-bicyclo 3.1.1!hept-2-enyl!methyl                   171        1-cyclohexenyl-4-isopropylmethyl                                    172        4- 4-methoxyphenyl!butyl                                            173        4-  2,3,4,5,6-pentamethyl!phenylsulfonyloxy!benzyl                  174        4- 1-pyrrolidinosulfonyl!benzyl                                     175        3- 4-methoxyphenyl!propyl                                           176        8-phenyloctyl                                                       177        4- 2,3-dihydroxypropoxy!benzyl                                      178        4- N-methylanilino!benzyl                                           179        2- 2-napthyl!ethyl                                                  189        6-methyl-2-naphthylmethyl                                           190        cis-bicyclo 3.3.0!octane-2-methyl                                   191        2-tridecynyl                                                        192        4-butyl-2-cyclohexylmethyl                                          193        4- (4-fluorobenzoyl)amino!benzyl                                    194        4- (3-fluorobenzoyl)amino!benzyl                                    195        8-phenoxyoctyl                                                      196        6-phenylhexyl                                                       197        10-phenyldecyl                                                      198        8-bromooctyl                                                        199        11-tridecynyl                                                       200        8- 4-methoxyphenoxy!octyl                                           201        8- 4-phenylphenoxy!octyl                                            202        8- 4-phenoxyphenoxy!octyl                                           203        3- 3-trifluoromethylphenoxy!benzyl                                  204        10-undecenyl                                                        205        4-cyclohexylbutyl                                                   206        4-phenyl-2-fluorobenzyl                                             207        7-hexadecynyl                                                       208        3- cyclopentyl!propyl                                               209        4- 2-methylphenyl!benzyl                                            210        4- phenylazo!benzyl                                                 211        4- 4-flurophenyl!benzyl                                             212        3-nitro-4- 4-nitrophenyl!benzyl                                     213        3-nitro-4- 2-nitrophenyl!benzyl                                     214        9-decenyl                                                           215        4- 3,4-dimethoxyphenyl!benzyl                                       216        4- 4-trifluromethylphenyl!benzyl                                    217        5-hexenyl                                                           218        4- 2-thienyl!benzyl                                                 219        4- 6-phenylhexyloxy!benzyl                                          220        9,10-dihydro-2-phenantrene methyl                                   221        4- 3,4-dimethylphenyl!benzyl                                        222        4- 4-methylphenyl!-2-methylbenzyl                                   223        4- 3-phenylpropyloxy!benzyl                                         224        4- 3-methylphenyl!benzyl                                            225        4- 4-methylphenyl!-3-methylbenzyl                                   226        4- 4-pentenyloxy!benzyl                                             227        4- 1-heptynyl!benzyl                                                228        3- 4-t-butyl-phenylthio!benzyl                                      229        4- 4-chlorophenyl!benzyl                                            230        4- 4-bromophenyl!benzyl                                             231        4- 4-cyanophenyl!benzyl                                             232        4- 1-nonynyl!benzyl                                                 233        4- 11-tridecynyloxy!benzyl                                          234        12-phenyldodecyl                                                    235        6-phenyl-5-hexynyl                                                  236        11-phenyl-10-undecynyl                                              237        4- 2-methylphenyl!-3-methylbenzyl                                   238        3- 2-thienyl!-2-thienylmethyl                                       239        4- benzyloxymethyl!cyclohexylmethyl                                 240        4- 4-chlorophenoxy!benzyl                                           241        4- benzyl!cyclohexylmethyl                                          242        4-benzoylbenzyl                                                     243        4- phenoxymethyl!benzyl                                             244        4- 4-chlorobenzyl!benzyl                                            ______________________________________                                    

                  TABLE 2B                                                         ______________________________________                                         COMPOUND     GLYCOPEPTIDE                                                      NO.          CORE           SIDECHAIN                                          ______________________________________                                         180          vancomycin     1-napthylmethyl                                    181          vancomycin     4-phenylbenzyl                                     182          A82846A        4-phenylbenzyl                                     183          A82846C        4-phenylbenzyl                                     184          A82846C        4-phenoxybenzyl                                    185          PA-42867 A     4-phenylbenzyl                                     186          reduced A83850A                                                                               4-phenylbenzyl                                     187          alpha-avoparcin                                                                               4-phenylbenzyl                                     188          beta-avoparcin 4-phenylbenzyl                                     ______________________________________                                    

                  TABLE 2C                                                         ______________________________________                                         COMPOUND                                                                       NO.       SIDECHAIN            R     R1  R3                                    ______________________________________                                         245       4-nitrobenzyl        x     x                                         246       8-benzyloctyl              x   x                                     247       4-phenoxybenzyl            x   x                                     248       4-phenylbenzyl       x     x                                         249       4-phenylbenzyl       x     x   x                                     250       4-phenylbenzyl                 x                                     251       4-phenylbenzyl             x   x                                     252       4- 4-chlorophenyl!benzyl       x                                     253       4- 4-chlorophenyl!benzyl   x   x                                     254       4- 4-chlorophenyl!benzyl                                                                            x     x                                         255       4- 4-chlorophenyl!benzyl                                                                            x     x   x                                     256       4-hydroxybenzyl            x   x                                     257       4-hydroxybenzyl                x                                     258       1,2,3,4-tetrahydro-6-naphthylmethyl                                                                       x   x                                     259       1,2,3,4-tetrahydro-6-naphthylmethyl                                                                           x                                     260       4- N-methylanilino!benzyl  x   x                                     261       3,3'-dichloro-4-hydroxy-benzyl                                                                            x   x                                     262       1,2,3,4-tetrahydro-9-anthranylmethyl                                                                      x   x                                     263       4- 4-nitrophenyl!benzyl                                                                             x     x                                         264       2-hydroxybenzyl      x     x                                         265       3,4-methylenedioxylbenzyl  x   x                                     266       3-benzyloxy-6-methoxy benzyl                                                                              x   x                                     267       4- 4-nitrophenoxy!benzyl   x   x                                     268       4-benzyloxy-3-methoxybenzyl                                                                               x   x                                     269       2,3-methylenedioxybenzyl   x   x                                     270       4-benzylbenzyl             x   x                                     271       3-phenoxybenzyl            x   x                                     272       4-trifluoromethylbenzyl                                                                             x     x                                         273       4- 1-oxa!fluorenylmethyl   x   x                                     274       4-pyridylmethyl            x   x                                     275       3-quinolylmethyl     x     x                                         276       2-benzthienylmethyl        x   x                                     277       4- 2-phenyl-6-methoxy!quinoylmethyl                                                                       x   x                                     278       4-thiomethylbenzyl   x     x                                         279       2-fluorenylmethyl    x     x                                         280       3-pyridylmethyl            x   x                                     281       2-pyridylmethyl            x   x                                     282       2-methoxy-1-napthylmethyl  x   x                                     283       9- 10-methyl!anthranylmethyl                                                                        x     x                                         284       9-anthranylmethyl          x   x                                     285       2-quinolylmethyl           x   x                                     286       5-nitro-1-naphthylmethyl                                                                            x         x                                     287       3,4 cyclohexenylmethyl     x   x                                     288       4- 2-t-butoxyethoxy!benzyl                                                                          x     x                                         ______________________________________                                    

The formula I compounds have in vitro and in vivo activity against Gram-positive pathogenic bacteria. The minimal inhibitory concentrations (MIC) at which the formula I compounds inhibit certain bacteria are given in Table 3. The MIC's were determined using a standard broth micro-dilution assay.

                                      TABLE 3                                      __________________________________________________________________________     In Vitro Activity of Formula I Compounds                                       MIC (mcg/ml)/Compound                                                          __________________________________________________________________________     Organism       vancomycin                                                                           A82846A                                                                             A82846B                                                                             A82846C                                                                             1   2    3   4    5   6                    __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5   0.25 0.25 0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   0.5                  Staphylococcus aureus 489                                                                     0.125 0.5  ≦.06                                                                         ≦.06                                                                         ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        0.5 0.25                 Staphylococcus aureus 447                                                                     0.5   0.25 0.25 0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 0.5 0.5                  Staphylococcus aureus X400                                                                    0.5   0.125                                                                               0.125                                                                               0.25 ≦0.06                                                                       1    ≦0.06                                                                       ≦0.06                                                                        1   1                    Staphylococcus aureus X778                                                                    0.5   0.125                                                                               0.125                                                                               0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 0.25                 Staphylococcus aureus 491                                                                     1     0.25 0.25 1    2   ≦0.06                                                                        0.5 ≦0.06                                                                        0.5 0.125                Staphylococcus aureus S13E                                                                    0.5   0.125                                                                               0.125                                                                               0.25 0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   0.25                 Staphylococcus aureus SA1199                                                                  0.5   0.125                                                                               0.125                                                                               0.25 ≦0.06                                                                       0.5  0.125                                                                              ≦0.06                                                                        1   0.25                 Staphylococcus aureus SA1199A                                                                 0.125 ≦.06                                                                         ≦.06                                                                         0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.5   ≦.06                                                                         0.125                                                                               ≦.06                                                                             ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06             Staphylococcus haemolyticus 105                                                               16    0.5  1    1    4   2    4   0.5  2   0.5                  Staphylococcus haemolyticus 415                                                               8     1    4    2    4   1    8   0.5  1   0.5                  Staphylococcus epidermidis 270                                                                16    0.25 0.25 0.25 8   8    8   ≦0.06                                                                        0.25                                                                               0.125                Entercoccus faecium 180                                                                       >64   16   8    16   0.5 0.25 0.5 0.125                                                                               ≦0.06                                                                       0.125                Entercoccus faecium 180-1                                                                     0.5   0.125                                                                               0.125                                                                               0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      2     0.125                                                                               0.25 0.5  0.125                                                                              0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       1     0.125                                                                               0.125                                                                               0.5  ≦0.06                                                                       0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Enterococcus gallinarum 245                                                                   4     0.125                                                                               0.25 0.5  4   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Haemophilus influenzae RD                                                                     >64   >64  >64  >64  >64                   >64                  Escherichia coli EC14                                                                         >64   >64  >64  >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   0.5             0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   0.25            ≦.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       7   8   9   10  11   12  13   14  15   16  17                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     8   2   2   16  4    32  2    4   1    4   2                    Staphylococcus aureus 489                                                                     2   4   0.5 >64 1    8   1    2   ≦0.06                                                                        0.5 1                    Staphylococcus aureus 447                                                                     4   8   4   >64 4    32  8    8   2    4   8                    Staphylococcus aureus X400                                                                    1   8   0.5 >64 0.5  8   1    4   0.25 0.5 0.5                  Staphylococcus aureus X778                                                                    0.25                                                                               8   0.25                                                                               16  0.25 8   2    4   0.25 2   0.5                  Staphylococcus aureus 491                                                                     2   4   0.5 16  1    4   2    1   0.25 1   2                    Staphylococcus aureus S13E                                                                    2   8   0.5 8   0.5  8   0.25 4   0.5  1   1                    Staphylococcus aureus SA1199                                                                  4   2   0.25                                                                               8   2    8   0.5  8   0.25 2   4                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       2   ≦0.06                                                                       4   ≦0.06                                                                        8   ≦0.06                                                                        0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 1       0.25                                                                               8   2        4    8   0.25 1   1                    Staphylococcus haemolyticus 105                                                               8   8   4   >64 4    16  8    4   0.5  8   8                    Staphylococcus haemolyticus 415                                                               16  8   4   >64 2    32  1    8   2    4   8                    Staphylococcus epidermidis 270                                                                4   4   16  >64 2    0.125                                                                              8    4   1    2   4                    Entercoccus faecium 180                                                                       2   1   1   8   1    4   2    1   0.5  1   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.5 ≦0.06                                                                       4   ≦0.06                                                                        4   ≦0.06                                                                        1   ≦0.06                                                                        0.125                                                                              ≦0.06         Entercoccus faecium 2041                                                                      0.125                                                                              4   0.25                                                                               16  0.5  16  0.125                                                                               2   ≦0.06                                                                        0.5 0.25                 Entercoccus faecium 276                                                                       1   4   0.26                                                                               18  1    4   0.5  4   ≦0.06                                                                        2   0.5                  Enterococcus gallinarum 245                                                                   0.5 8   0.25                                                                               8   ≦0.06                                                                        32  0.25 0.25                                                                               ≦0.06                                                                        1   0.5                  Haemophilus influenzae RD                                                                     16  >64 ≦0.06 64  32                32                   Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       18  19  20  21  22   23  24   25  26   27  28                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   0.5 0.5 >64 16   38  0.5  0.5 0.25 2   0.25                 Staphylococcus aureus 489                                                                     1   0.25                                                                               0.5 32  8    >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     8   1   4   >64 16   16  1    0.25                                                                               2    8   1                    Staphylococcus aureus X400                                                                    1   0.25                                                                               0.5 32  8    16  0.25 ≦0.06                                                                       0.25 0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 0.25                                                                               0.25                                                                               32  8    16  0.125                                                                               ≦0.06                                                                       0.125                                                                               0.5 ≦0.06         Staphylococcus aureus 491                                                                     2   2   1   64  8    16  0.5  0.125                                                                              0.5  1   0.25                 Staphylococcus aureus S13E                                                                    1   ≦0.06                                                                       ≦0.06                                                                       64  16   16  ≦0.06                                                                        ≦0.06                                                                       0.25 0.125                                                                              ≦0.06         Staphylococcus aureus SA1199                                                                  2   0.5 2   64  16   16  0.5  ≦0.06                                                                       1    0.5 0.125                Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       16  4    16  ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   1   0.5 64  16   16  2    0.125                                                                              0.5  1   0.125                Staphylococcus haemolyticus 105                                                               16  4   8   >64 16   4   4    1   4    16  4                    Staphylococcus haemolyticus 415                                                               8   8   4   64  16   16  ≦0.06                                                                        32  8    8   8                    Staphylococcus epidermidis 270                                                                8   2   2   32  4    64  1    0.5 1    4   1                    Entercoccus faecium 180                                                                       2   1   1   8   1    >64 4    0.5 4    8   1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       8   ≦0.06                                                                        32  ≦0.06                                                                        ≦0.06                                                                       0.25 0.5 ≦0.06         Entercoccus faecium 2041                                                                      0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       32  2    32  ≦0.06                                                                        0.25                                                                               0.25 0.125                                                                              0.25                 Entercoccus faecium 276                                                                       1   ≦0.06                                                                       0.25                                                                               64  4    32  0.25 0.25                                                                               ≦0.06                                                                        0.5 ≦0.06         Enterococcus gallinarum 245                                                                   1   ≦0.06                                                                       0.25                                                                               8   1    8   0.25 ≦0.06                                                                       0.125                                                                               0.5 0.25                 Haemophilus influenzae RD                                                                     16  32  8   >64 64   >64 >64  32  >64  >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       2   ≦0.06                                                                        1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06             Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5 0.25 0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06             __________________________________________________________________________     Organism       29  30  31  32  33   34  35   36  37   38  39                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   1   0.5 1   4    32  0.5  8   0.5  0.5 0.125                Staphylococcus aureus 489                                                                     1   0.125                                                                              ≦0.06                                                                       1   ≦0.06                                                                        8   ≦0.06                                                                        2   0.125                                                                               ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     0.25                                                                               2   0.5 0.5 0.125                                                                               8   0.125                                                                               2   0.125                                                                               0.125                                                                              0.25                 Staphylococcus aureus X400                                                                    0.25                                                                               ≦0.06                                                                       0.125                                                                              0.5 0.25 32  0.25 4   0.25 1   ≦0.06         Staphylococcus aureus X778                                                                    ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              0.5 0.5  16  ≦0.06                                                                        2   ≦0.06                                                                        0.5 ≦0.06         Staphylococcus aureus 491                                                                     0.25                                                                               0.5 0.5 0.25                                                                               0.125                                                                               8   0.125                                                                               1   0.25 0.5 0.25                 Staphylococcus aureus S13E                                                                    1   0.125                                                                              0.25                                                                               1   ≦0.06                                                                        16  ≦0.06                                                                        2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               0.5 0.25                                                                               1   1    16  0.25 4   0.25 1   ≦0.06         Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.25                                                                               0.125                                                                              0.25                                                                               0.125                                                                              0.125                                                                               16  0.25 4   ≦0.06                                                                        0.125                                                                              ≦0.06         Staphylococcus haemolyticus 105                                                               4   4   4   4   2    32  2    4   0.25 1   2                    Staphylococcus haemolyticus 415                                                               1   16  16  4   8    >64 4    8   1    1   4                    Staphylococcus epidermidis 270                                                                0.5 2   1   1   2    16  1    2   0.25 0.5 0.25                 Entercoccus faecium 180                                                                       0.25                                                                               2   4   0.25                                                                               2    4   1    0.25                                                                               0.125                                                                               ≦0.06                                                                       0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        2   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      0.25                                                                               ≦0.06                                                                       0.25                                                                               0.25                                                                               ≦0.06                                                                        8   ≦0.06                                                                        1   0.125                                                                               ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       0.25                                                                               0.25                                                                               0.25                                                                               0.125                                                                              ≦0.06                                                                        16  ≦0.06                                                                        2   1    0.5 ≦0.06         Enterococcus gallinarum 245                                                                   0.25                                                                               ≦0.06                                                                       0.25                                                                               0.25                                                                               0.25 4   ≦0.06                                                                        0.25                                                                               0.125                                                                               0.125                                                                              ≦0.06         Haemophilus influenzae RD                                                                     >64 >64 >64 >64                                                 Escherichia coli EC14                                                                         64  >64 >64 32  >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                      ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                      ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       51  52  53  54  55   56  57   58  59   60  61                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.25                                                                               ≦0.06                                                                       2   1   0.5  0.5 0.25 0.25                                                                               0.5  1   0.5                  Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.5 2   ≦0.06                                                                       1    1   0.5  ≦0.06                                                                       0.125                                                                               0.5 1                    Staphylococcus aureus 447                                                                     0.5 ≦0.06                                                                       4   0.25                                                                               4    2   0.5  1   1    2   2                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       4   ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       0.25 0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 0.5 2   ≦0.06                                                                       0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.125                Staphylococcus aureus 491                                                                     0.25    2       0.5  0.5      0.125    1   0.5                  Staphylococcus aureus S13E                                                                    0.5 0.5 2   0.5 0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               0.25                                                                               0.125                Staphylococcus aureus SA1199                                                                  0.5 2   2   0.5 0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               0.25                                                                               0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       1   ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 1   2   2   1   0.5  0.5 0.125                                                                               0.125                                                                              0.5  0.5 0.25                 Staphylococcus haemolyticus 105                                                               0.5 0.5 2   2   4    4   8    4   8    >64 64                   Staphylococcus haemolyticus 415                                                               1   1   2   1   16   16  1    8   8    16  8                    Staphylococcus epidermidis 270                                                                0.5 0.5 2   0.25                                                                               1    1   0.5  4   1    2   1                    Entercoccus faecium 180                                                                       0.5 2   1   1   2    2   0.5  8   8    4   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       2   ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.5 1   ≦0.06                                                                       0.125                                                                               0.25                                                                               ≦0.06                                                                        0.5 0.5  0.25                                                                               ≦0.06         Entercoccus faecium 276                                                                       ≦0.06                                                                       0.125                                                                              8   1   0.5  0.25                                                                               0.5  0.5 0.125                                                                               0.5 0.25                 Enterococcus gallinarum 245                                                                   1   1   2   0.5 16   16  2    0.4 1    16  8                    Haemophilus influenzae RD                                                                     >64 >64 >64     >64  >64 >64  >64 >64  >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                  Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       62  63  64  65  66   67  68   69  70   71  72                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   0.5 0.25                                                                               2   0.25 0.25                                                                               0.125                                                                               1   0.125                                                                               4   2                    Staphylococcus aureus 489                                                                     2   8   0.25                                                                               0.125                                                                              1    ≦0.06                                                                       0.125                                                                               0.25                                                                               ≦0.06                                                                        0.25                                                                               ≦0.06         Staphylococcus aureus 447                                                                     0.5 1   0.5 1   1    1   0.25 1   0.5  4   1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              0.125                                                                              0.125                                                                               1   ≦0.06                                                                        0.5 ≦0.06                                                                        1   0.125                Staphylococcus aureus X778                                                                    0.5 0.125                                                                              2   0.5 ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        2   0.25                 Staphylococcus aureus 491                                                                     0.125                                                                              0.5 0.125                                                                              0.5 0.25 1   0.125                                                                               1   0.5  2   0.25                 Staphylococcus aureus S13E                                                                    0.5 0.125                                                                              2   0.5 ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        1   ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               0.25                                                                               1   0.5 0.25 1   ≦0.06                                                                        1   ≦0.06                                                                        1   1                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06         Staphylococcus aureus SA1199B                                                                 1   0.5 0.125                                                                              2   0.25 1   0.5  2   ≦0.06                                                                        4   ≦0.06         Staphylococcus haemolyticus 105                                                               2   4   64  64  64   64  2    4   2    16  1                    Staphylococcus haemolyticus 415                                                               4   8   2   4   8    2   4    8   2    8   4                    Staphylococcus epidermidis 270                                                                1   1   0.5 1   1    0.5 2    2   0.25 2   0.25                 Entercoccus faecium 180                                                                       4   16  0.125                                                                              0.5 2    0.25                                                                               2    4   0.5  4   0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06                                                                        1   ≦0.06         Entercoccus faecium 276                                                                       0.5 0.5 0.5 0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 ≦0.06                                                                        2   ≦0.06         Enterococcus gallinarum 245                                                                   4   8   2   4   8    2   4    8   2    8   4                    Haemophilus influenzae RD                                                                     >64 >64 >64 >64 >64  >64 >64  >64 16   >64 32                   Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pygoenes C203                                                                   ≦0.06                                                                       ≦0.06                                                Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                               __________________________________________________________________________     Organism       73  74  75  76  77   78  79   80  81   82  83                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.25                                                                               4   2   0.25                                                                               ≦0.06                                                                        2   2    4   2    2   1                    Staphylococcus aureus 489                                                                     0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2    2   2    0.25                                                                               0.25                 Staphylococcus aureus 447                                                                     0.25                                                                               1   1   0.5 1    ≦0.06                                                                       2    2   2    4   2                    Staphylococcus aureus X400                                                                    0.5 ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.25 4   1    0.25                                                                               2                    Staphylococcus aureus X778                                                                    1   ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       2    0.5 1    0.5 0.5                  Staphylococcus aureus 491                                                                     0.25                                                                               0.125                                                                              0.25                                                                               0.25     0.25                                                                               4    1   1    1   0.5                  Staphylococcus aureus S13E                                                                        0   0       0.125    4    1   0.5  ≦0.06                                                                       0.125                Staphylococcus aureus SA1199                                                                  0.5 ≦0.06                                                                       2   ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              1    2   2    0.25                                                                               2                    Staphylococcus aureus SA1199A                                                                 0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               1   0.5  0.5 0.25                 Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       1   0.5 0.25                                                                               0.125                                                                               ≦0.06                                                                       1    1   1    1   1                    Staphylococcus haemolyticus 105                                                               0.5 4   2   2   2    2   4    4   1    8   2                    Staphylococcus haemolyticus 415                                                               2   4   4   4   8    16  4    4   4    8   4                    Staphylococcus epidermidis 270                                                                0.125                                                                              0.5 0.5 0.25                                                                               0.5  0.5 0.5  2   1    4   2                    Entercoccus faecium 180                                                                       0.5 0.5 0.5 0.5 8    1   ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        2   8                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               0.125                                                                              0.125                Entercoccus faecium 2041                                                                      0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 0.5                  Entercoccus faecium 276                                                                       0.25    ≦0.06                                                                       ≦0.06                                                                       0.25 0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06             Enterococcus gallinarum 245                                                                   2   ≦0.06                                                                       4   4   0.25 0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       0.25 0.125                                                                              0.5                  Haemophilus influenzae RD                                                                     0.25                                                                               0.5 2   >64 64       16   16  16   64  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       84  85  86  87  88   89  90   91  92   93  94                   __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.125                                                                              1   1   0.25 0.5 2    0.5 2    2   1                    Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.25                                                                               1   0.5 0.5  0.25                                                                               2    ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               2                    Staphylococcus aureus 447                                                                     4   0.125                                                                              0.5 0.5 0.25 1   1    0.5 0.5  0.25                                                                               0.5                  Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.25                                                                               1   1   ≦0.06                                                                        0.25                                                                               1    0.5 0.5  ≦0.06                                                                       1                    Staphylococcus aureus X778                                                                    ≦0.06                                                                       0.25                                                                               1   2   0.5  0.25                                                                               1    ≦0.06                                                                       0.25 1   0.5                  Staphylococcus aureus 491                                                                     1   0.125                                                                              1   2   0.5  1   2    1   1    0.25                                                                               0.5                  Staphylococcus aureus S13E                                                                    0.125                                                                              0.5 1   0.5 1    0.25                                                                               1    ≦0.06                                                                       0.125                                                                               1   2                    Staphylococcus aureus SA1199                                                                  0.25                                                                               0.5 0.5 2   1    0.5 2    ≦0.06                                                                       1    2   0.5                  Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.5 1   1   0.5 1    1   1    0.5 0.5  1   2                    Staphylococcus haemolyticus 105                                                               8   1   1   1   1    1   2    2   2    1   2                    Staphylococcus haemolyticus 415                                                               16  2   1   2   2    2   2    2   2    1   2                    Staphylococcus epidermidis 270                                                                1   0.5 1   1   1    1   1    0.5 1    1   1                    Entercoccus faecium 180                                                                       4   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               0.125                                                                              0.25 0.5 0.125                                                                               ≦0.06                                                                       0.25                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                           0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2    ≦0.06                                                                       0.125                                                                               0.25                                                                               0.125                Enterococcus gallinarum 245                                                                   0.25                                                                               2   1   2   ≦0.06                                                                        ≦0.06                                                                       2    2   2    1   2                    Haemophilus influenzae RD               >64                                    Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       95  96  97  98  99   100 101  102 103  104 105                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 1   1   0.5 0.5  1   0.5  1   0.5  ≦0.06                                                                       0.25                 Staphylococcus aureus 489                                                                     2   1   0.25                                                                               ≦0.06                                                                       0.25 0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5                  Staphylococcus aureus 447                                                                     0.5 1   1   0.25                                                                               2    0.5 1    1   1    0.25                                                                               0.5                  Staphylococcus aureus X400                                                                    1   2   1   ≦0.06                                                                       0.125                                                                               1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.5                  Staphylococcus aureus X778                                                                    1   1   0.25                                                                               ≦0.06                                                                       0.5  1   0.25 ≦0.06                                                                       0.5  ≦0.06                                                                       0.5                  Staphylococcus aureus 491                                                                     1   1   0.5 0.25                                                                               1    ≦0.06                                                                       0.5  1   1    ≦0.06                                                                       0.25                 Staphylococcus aureus S13E                                                                    2   1   >64 0.5 0.5  1   0.25 1   1    ≦0.06                                                                       0.5                  Staphylococcus aureus SA1199                                                                  0.5 2   2   0.5 0.5  0.5 0.25 0.125                                                                              1    2   1                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5  0.125                                                                              0.5  ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25                 Staphylococcus aureus SA1199B                                                                 1   1   1   1   0.5  0.5 1    1   2    0.125                                                                              0.5                  Staphylococcus haemolyticus 105                                                               1   2   2   1   8    1   1    2   4    2   1                    Staphylococcus haemolyticus 415                                                               1   2   2   1   32   2   8    4   8    2   1                    Staphylococcus epidermidis 270                                                                1   2   1   ≦0.06                                                                       1    0.5 0.5  1   1    0.25                                                                               0.25                 Entercoccus faecium 180                                                                       0.5 0.5                                ≦0.06                                                                       0.25                 Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       1   ≦0.06                                                                       ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25                 Entercoccus faecium 276                                                                       0.125                                                                              0.5 ≦0.06                                                                       0.125                                                                              0.25 0.25                                                                               0.125                                                                               0.25                                                                               0.25 ≦0.06                                                                       0.25                 Enterococcus gallinarum 245                                                                   1   2   2   1   32   2   8    4   8    2   1                    Haemophilus influenzae RD      >64  >64 >64           32  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       106 107 108 100 110  111 112  113 114  115 116                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     2   2   2   1   0.5  2   2    ≦0.06                                                                       0.5  0.125                                                                              0.5                  Staphylococcus aureus 489                                                                     2   1   0.25                                                                               ≦0.06                                                                       1    1   0.25 0.125                                                                              1    0.125                                                                              1                    Staphylococcus aureus 447                                                                     0.25                                                                               1   0.5 1   1    1   1    0.25                                                                               0.5  0.5 1                    Staphylococcus aureus X400                                                                    1   1   2   ≦0.06                                                                       1    1   1    0.125                                                                              2    1   1                    Staphylococcus aureus X778                                                                    1   0.5 0.125                                                                              ≦0.06                                                                       0.5  2   1    1   2    1   2                    Staphylococcus aureus 491                                                                     0.5 1   0.25                                                                               0.25                                                                               0.25 2   1    0.25                                                                               1    0.5 0.5                  Staphylococcus aureus S13E                                                                    1   2   1   0.25                                                                               1    1   1    ≦0.06                                                                       2    0.25                                                                               1                    Staphylococcus aureus SA1199                                                                  1   1   2   ≦0.06                                                                       0.25 2   2    1   2    0.125                                                                              4                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.5 0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   2   2   0.5 0.5  1   0.5  ≦0.06                                                                       1    0.25                                                                               0.5                  Staphylococcus haemolyticus 105                                                               1   2   2   1   4    1   2    4   2    1   2                    Staphylococcus haemolyticus 415                                                               1   2   1   4   2    4   2    1   2    2   4                    Staphylococcus epidermidis 270                                                                0.25                                                                               0.5 0.125                                                                              0.25                                                                               2    1   1    0.25                                                                               1    0.5 1                    Entercoccus faecium 180                                                                       ≦0.06                                                                       0.125                                                                              0.125                                                                              0.25                                                                               0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      0.125                                                                              0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       0.5 1   0.5 ≦0.06                                                                       0.5  0.5 0.5  0.25                                                                               1    0.125                                                                              0.25                 Enterococcus gallinarum 245                                                                   1   2   ≦0.06                                                                       ≦0.06                                                                       2    4   2    1   2    2   4                    Haemophilus influenzae RD                                                                     >64 >64 >64 32  >64  >64 >64  >64 >64  >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64     >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                           ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                           ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       117 118 119 120 121  122 123  124 125  126 127                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 1   2   2   2    1   2    4   4    2   1                    Staphylococcus aureus 489                                                                     0.125                                                                              0.25                                                                               0.5 2   1    ≦0.06                                                                       2    0.25                                                                               2    0.25                                                                               2                    Staphylococcus aureus 447                                                                     0.5 0.25                                                                               2   1   0.5  0.25                                                                               1    0.25                                                                               2    1   2                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.25                                                                               1   0.25                                                                               0.125                                                                               ≦0.06                                                                       1    1   1    1   2                    Staphylococcus aureus X778                                                                    0.25                                                                               0.5 2   0.125                                                                              0.5  ≦0.06                                                                       1    0.5 2    0.5 1                    Staphylococcus aureus 491                                                                     0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              1    0.25                                                                               1                    Staphylococcus aureus S13E                                                                    ≦0.06                                                                       0.25                                                                               0.25                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1    0.5 2                    Staphylococcus aureus SA1199                                                                  ≦0.06                                                                       2   2   1   1    ≦0.06                                                                       2    1   0.5  0.125                                                                              2                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       0.25 0.25                                                                               0.25                 Staphylococcus aureus SA1199B                                                                 0.5 ≦0.06                                                                       0.5 0.125                                                                              0.25 ≦0.06                                                                       0.5  ≦0.06                                                                       2    1   2                    Staphylococcus haemolyticus 105                                                               1   1   2   2   2    1   2    2   4    0.5 2                    Staphylococcus haemolyticus 415                                                               2   1   2   2   2    1   1    1   2    2   4                    Staphylococcus epidermidis 270                                                                0.5 1   2   2   1    ≦0.06                                                                       1    0.25                                                                               1    1   ≦0.06         Entercoccus faecium 180                                                                       1   0.125                                                                              0.125                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       1    1   ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       0.25                                                                               ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       2    1   ≦0.06         Enterococcus gallinarum 245                                                                   2   1   2   2   2    1   1    1   12   2   4                    Haemophilus influenzae RD                                                                         16  16  16  16   16  16   16           >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       128 129 130 131 132  133 134  135 136  137 138                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     4   2   1   2   1    2   2    1   ≦0.06                                                                        0.25                                                                               0.125                Staphylococcus aureus 489                                                                     1   ≦0.06                                                                       0.5 1   1    1   0.5  0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus 447                                                                     1   1   1   1   2    1   1    1   2    4   2                    Staphylococcus aureus X400                                                                    1   0.25                                                                               0.5 1   1    0.5 0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.0606       Staphylococcus aureus X778                                                                    1   0.25                                                                               1   0.5 2    2   1    1   ≦0.06                                                                        ≦0.06                                                                       0.25                 Staphylococcus aureus 491                                                                     2   0.5 0.5 0.125                                                                              0.5  0.25                                                                               0.5  0.25                                                                               0.25 0.25                                                                               0.125                Staphylococcus aureus S13E                                                                    1   0.25                                                                               0.5 1   2    1   2    1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199                                                                  0.5 0.25                                                                               1   0.25                                                                               1    0.25                                                                               0.25 1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199A                                                                 0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.25 0.25                                                                               0.25 ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   0.25                                                                               2   1   2    2   2    0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.5                  Staphylococcus haemolyticus 105                                                               1   4   1   1   1    2   2    0.5 2    2   4                    Staphylococcus haemolyticus 415                                                               2   4   2   2   2    2   4    2   4    8   8                    Staphylococcus epidermidis 270                                                                1   1   1   1   2    1   2    0.5 1    0.5 2                    Entercoccus faecium 180                                                                       1   4   1   ≦0.06                                                                       0.25 1   0.5  1   2    0.125                                                                              4                    Entercoccus faecium 180-1                                                                     0.125                                                                              ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      0.5 ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       1    0.25                                                                               0.25 0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       1   0.125                                                                              1   0.25                                                                               1    1   1    0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Enterococcus gallinarum 245                                                                   2   0.125                                                                              2   2   2    2   4    2   4    8   0.125                Haemophilus influenzae RD                                                                         >64                                                         Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       139 140 141 142 143  144 145  146 147  148 149                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.125                                                                              2   2   0.5  16  0.5  0.5 0.5  1   0.5                  Staphylococcus aureus 489                                                                     0.25                                                                               ≦0.06                                                                       0.25                                                                               0.5 ≦0.06                                                                        4   ≦0.06                                                                        0.25     0.25                                                                               ≦0.06         Staphylococcus aureus 447                                                                     1   0.25                                                                               1   2   4    16  1    2   0.125                                                                               1   4                    Staphylococcus aureus X400                                                                    0.25                                                                               ≦0.06                                                                       0.25                                                                               1   0.125                                                                               8   0.25 0.5 4    ≦0.06                                                                       ≦0.06         Staphylococcus aureus X778                                                                    0.125                                                                              0.25                                                                               0.5 1   ≦0.06                                                                        8   0.125                                                                               ≦0.06                                                                       0.25 2   0.5                  Staphylococcus aureus 491                                                                     0.5 0.25                                                                               0.5 0.5 0.5  8   0.5  1   ≦0.06                                                                        0.125                                                                              0.5                  Staphylococcus aureus S13E                                                                    ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               2   0.125                                                                               8   0.125                                                                               0.5 1    1   0.25                 Staphylococcus aureus SA1199                                                                  0.125                                                                              ≦0.06                                                                       0.25                                                                               1   0.125                                                                               8   0.25 ≦0.06                                                                       0.5  2   0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 2   ≦0.06                                                                       2   2   0.25 8   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 1                    Staphylococcus haemolyticus 105                                                               4   2   1   1   8    64  2    2   1    1   4                    Staphylococcus haemolyticus 415                                                               8   8   4   1   32   >64 8    4   8    2   16                   Staphylococcus epidermidis 270                                                                1   0.25                                                                               1   0.25                                                                               1    16  1    2   16   0.5 1                    Entercoccus faecium 180                                                                       2   1   0.5 0.5 4    8   4    8   2    0.25                                                                               1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        4   ≦0.06                                                                        ≦0.06                                                                       2    ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               8   0.25 0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       1   0.5 0.5 1   0.25 8   0.125                                                                               1   0.125                                                                               ≦0.06                                                                       ≦0.06         Enterococcus gallinarum 245                                                                   8   8   4   1   32   4   0.25 0.5 0.125                                                                               2   16                   Haemophilus influenzae RD                    >64                               Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       150 151 152 153 154  155 156  157 158  159 160                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   2   2   0.5 2    2   2    0.5 2    0.5 2                    Staphylococcus aureus 489                                                                     0.5 ≦0.06                                                                       0.5 1   1    0.5 1    0.5 2    0.25                                                                               0.21                 Staphylococcus aureus 447                                                                     0.5 1   8   0.5 2    8   1    0.25                                                                               4    4   1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       ≦0.06                                                                       1   0.5 2    1   2    0.5 4    4   4                    Staphylococcus aureus X778                                                                    2   1   0.5 0.5 0.5  ≦0.06                                                                       1    0.25                                                                               4    2   4                    Staphylococcus aureus 491                                                                     ≦0.06                                                                       0.5 1   0.125                                                                              0.5  1   1    ≦0.06                                                                       1    2   0.125                Staphylococcus aureus S13E                                                                    0.25                                                                               0.25                                                                               0.5 0.125                                                                              0.25 1   1    0.25                                                                               2    1   1                    Staphylococcus aureus SA1199                                                                  1   0.125                                                                              1   0.5 2    1   1    1   4    0.125                                                                              0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.25                                                                               ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1    ≦0.06                                                                       0.125                Staphylococcus aureus SA1199B                                                                 0.5 0.25                                                                               0.5 0.25                                                                               0.25 1   0.5  1   4    ≦0.06                                                                       ≦0.06         Staphylococcus haemolyticus 105                                                               1   1   16  2   4    16  4    1   4    16  8                    Staphylococcus haemolyticus 415                                                               2   4   16  1   4    16  2    1   8    8   8                    Staphylococcus epidermidis 270                                                                0.25                                                                               0.5 4   0.25                                                                               0.5  1   1    0.25                                                                               4    0.5 1                    Entercoccus faecium 180                                                                       0.25                                                                               0.25                                                                               4   0.125                                                                              1    4   1    ≦0.06                                                                       0.25 2   0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.25 ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       ≦0.06                                                                       0.125                                                                              ≦0.06                                                                       0.125                                                                               0.125                                                                              0.5  ≦0.06                                                                       1    0.125                                                                              ≦0.06         Entercoccus faecium 276                                                                       1   ≦0.06                                                                       0.25                                                                               0.5 0.5  0.25                                                                               2    ≦0.06                                                                       2    0.125                                                                              2                    Enterococcus gallinarum 245                                                                   2   4   16  1   4    16  2    1   8    8   8                    Haemophilus influenzae RD           16  2                                      Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       161 162 163 164 165  166 167  168 169  170 171                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 0.5 1   2   1    2   1    ≦0.06                                                                       0.25 2   1                    Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.25                                                                               8   2   2    2   16   0.125                                                                              ≦0.06                                                                        0.25                                                                               0.5                  Staphylococcus aureus 447                                                                     1   ≦0.06                                                                       0.5 2   0.5  2   4    ≦0.06                                                                       2    0.5 1                    Staphylococcus aureus X400                                                                    0.5 ≦0.06                                                                       0.5 0.5 0.5  1   1    ≦0.06                                                                       ≦0.06                                                                        0.5 ≦0.06         Staphylococcus aureus X778                                                                    0.5 ≦0.06                                                                       2   1   0.125                                                                               1   16   0.5 ≦0.06                                                                        1   ≦0.06         Staphylococcus aureus 491                                                                     0.5 0.25                                                                               ≦0.06                                                                       1   0.5  0.5 2    0.5 0.25 0.5 0.25                 Staphylococcus aureus S13E                                                                    0.125                                                                              ≦0.06                                                                       1   4   ≦0.06                                                                        4   4    ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               ≦0.06                                                                       2   2   0.25 2   2    0.5 ≦0.06                                                                        1   0.25                 Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       0.5 0.5 ≦0.06                                                                        0.125                                                                              4    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 0.25                                                                               ≦0.06                                                                       1   2   1    2   4    1   0.125                                                                               0.25                                                                               0.25                 Staphylococcus haemolyticus 105                                                               4   0.25                                                                               8   2   4    2   32   0.5 2    4   4                    Staphylococcus haemolyticus 415                                                               8   2   8   2   4    2   16   2   4    4   8                    Staphylococcus epidermidis 270                                                                1   ≦0.06                                                                       4   1   1    0.5 8    0.125                                                                              0.25 1   1                    Entercoccus faecium 180                                                                       2   ≦0.06                                                                       1   0.5 0.5  0.25                                                                               2    0.25                                                                               1    2   1                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       ≦0.06                                                                       1   1   ≦0.06                                                                        ≦0.06                                                                       8    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       0.125                                                                              ≦0.06                                                                       1   1   0.5  0.5 4    0.125                                                                              ≦0.06                                                                        0.5 0.125                Enterococcus gallinarum 245                                                                   8   2   8   2   4    2   16   2   4    4   8                    Haemophilus influenzae RD                             >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       172 173 174 175 176  177 178  179 180  181 182                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     4   4   0.5 1   2    0.5 1    0.125                                                                              0.125                                                                               ≦0.06                                                                       2                    Staphylococcus aureus 489                                                                     0.5 2   ≦0.06                                                                       0.25                                                                               0.5  ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2                    Staphylococcus aureus 447                                                                     0.5 4   4   1   1    4   0.5  0.25                                                                               0.125                                                                               ≦0.06                                                                       0.25                 Staphylococcus aureus X400                                                                    0.5 4   ≦0.06                                                                       0.125                                                                              1    ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       1                    Staphylococcus aureus X778                                                                    2   4   ≦0.06                                                                       0.5 1    2   1    ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       2                    Staphylococcus aureus 491                                                                     0.5 2   1   0.5 2    0.5 0.125                                                                               0.125                                                                              0.5      1                    Staphylococcus aureus S13E                                                                    ≦0.06                                                                       4   ≦0.06                                                                       0.25                                                                               2    0.25                                                                               0.5  0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.25                 Staphylococcus aureus SA1199                                                                  1   2   ≦0.06                                                                       ≦0.06                                                                       2    0.25                                                                               1    1   0.125                                                                               ≦0.06                                                                       2                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       0.5 ≦0.06                                                                       0.5 >64  0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       4   0.125                                                                              ≦0.06                                                                       1    0.25                                                                               1    0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       4                    Staphylococcus haemolyticus 105                                                               0.25                                                                               2   4   2   4    4   1    0.5 2    0.25                                                                               2                    Staphylococcus haemolyticus 415                                                               2   4   16  4   2    16  2    1   2    1   4                    Staphylococcus epidermidis 270                                                                0.5 2   2   0.5 0.5  1   0.25 0.25                                                                               0.125                                                                               0.125                                                                              0.25                 Entercoccus faecium 180                                                                       0.5 0.5 2   1   2    4   0.25 ≦0.06                                                                       8    4   2                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.5 ≦0.06                                                                       ≦0.06                                                                       0.125                                                                               0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.25 0.125                                                                              1                    Entercoccus faecium 276                                                                       0.125                                                                              2   ≦0.06                                                                       ≦0.06                                                                       2    0.25                                                                               0.5  ≦0.06                                                                       2    2   1                    Enterococcus gallinarum 245                                                                   2   4   16  4   2    16  2    1   0.25 ≦0.06                                                                       1                    Haemophilus influenzae RD                                                                     32  >64 >64 16  8    >64 4    4        32  >64                  Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5 0.25 16  ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       0.5 0.25 8   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       183 184 185 186 189  190 191  192 193  194 195                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     ≦0.06                                                                       2   ≦.06                                                                        ≦.06                                                                        0.5  0.25                                                                               2    0.5 0.5  ≦0.06                                                                       0.5                  Staphylococcus aureus 489                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                        1    0.125                                                                              2    1   0.125                                                                               0.125                                                                              1                    Staphylococcus aureus 447                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                        0.5  1   2    2   ≦0.06                                                                        0.5 1                    Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.5 ≦.06                                                                        ≦.06                                                                        0.125                                                                               ≦0.06                                                                       1    1   0.25 ≦0.06                                                                       2                    Staphylococcus aureus X778                                                                    ≦0.06                                                                       0.5 ≦.06                                                                        ≦.06                                                                        0.25 0.125                                                                              2    1   ≦0.06                                                                        0.5 0.5                  Staphylococcus aureus 491                                                                     0.125                                                                              0.5 ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        0.125                                                                              1    0.5 ≦0.06                                                                        ≦0.06                                                                       0.5                  Staphylococcus aureus S13E                                                                    ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                        0.5  0.125                                                                              2    1   ≦0.06                                                                        ≦0.06                                                                       2                    Staphylococcus aureus SA1199                                                                  ≦0.06                                                                       0.125                                                                              ≦.06                                                                        ≦.06                                                                        0.5  0.25                                                                               2    2   0.125                                                                               0.5 0.5                  Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        ≦0.06                                                                       0.5  0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                        1    0.5 2    0.5 0.125                                                                               0.125                                                                              1                    Staphylococcus haemolyticus 105                                                               ≦0.06                                                                       0.25                                                                               ≦.06                                                                        0.5 1    8   2    1   0.5  1   1                    Staphylococcus haemolyticus 415                                                               ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        1   1    8   8    2   1    2   4                    Staphylococcus epidermidis 270                                                                ≦0.06                                                                       4   ≦.06                                                                        0.125                                                                              0.25 2   2    1   0.25 0.5 0.25                 Entercoccus faecium 180                                                                       2   8   0.125                                                                              2   0.125                                                                               8   4    0.25                                                                               ≦0.06                                                                        ≦0.06                                                                       0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦.06                                                                        ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        ≦0.06                                                                       0.25 0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       1   ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        ≦0.06                                                                       1    0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 276                                                                       0.125                                                                              0.5 ≦.06                                                                        ≦.06                                                                        0.25 0.125                                                                              4    0.5 ≦0.06                                                                        0.125                                                                              0.25                 Enterococcus gallinarum 245                                                                   0.5 4   ≦.06                                                                        2   1    8   8    2   1    2   4                    Haemophilus influenzae RD                                                                     >64 64  8       32   >64 >64  >64 >64  >64 32                   Escherichia coli EC14                                                                         >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                           ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                           ≦.06                                                                        ≦.06                                                                        ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       196 197   198 199   200 201   202 203  204 205                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 1     1   0.5   1   4     4   0.5  0.125                                                                              2                    Staphylococcus aureus 489                                                                     1   2     0.125                                                                              2     0.25                                                                               8     4   0.5  0.25                                                                               0.5                  Staphylococcus aureus 447                                                                     0.5 2     0.125                                                                              1     0.5 16    8   1    ≦0.06                                                                       0.5                  Staphylococcus aureus X400                                                                    0.5 2     0.5 2     1   4     4   1    0.125                                                                              0.5                  Staphylococcus aureus X778                                                                    1   2     0.125                                                                              1     0.5 4     4   1    0.5 0.5                  Staphylococcus aureus 491                                                                     0.25                                                                               1     ≦0.06                                                                       0.5   0.125                                                                              4     4   1    0.5 0.5                  Staphylococcus aureus S13E                                                                    1   2     0.125                                                                              0.5   0.5 8     4   2    0.5 0.5                  Staphylococcus aureus SA1199                                                                  0.5 2     0.5 1     1   8     8   2    0.125                                                                              1                    Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       1     ≦0.06                                                                       0.125 ≦0.06                                                                       2     2   0.5      ≦0.06         Staphylococcus aureus SA1199B                                                                 0.5 2     0.5 1     1   16    8   1    0.25                                                                               0.5                  Staphylococcus haemolyticus 105                                                               0.5 1     0.5 2     1   8     4   1    0.5 1                    Staphylococcus haemolyticus 415                                                               1   4     1   4     2   8     8   2    0.25                                                                               1                    Staphylococcus epidermidis 270                                                                0.25                                                                               0.5   0.25                                                                               0.5   0.25                                                                               4     4   0.5  ≦0.06                                                                       0.125                Entercoccus faecium 180                                                                       0.5 0.5   ≦0.06                                                                       0.5   0.25                                                                               0.5   0.5 0.125                                                                               0.25                                                                               0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.25  ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       0.5   0.5 ≦0.06                                                                        0.125                                                                              ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.25  ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       1     1   0.25 ≦0.06                                                                       0.25                 Entercoccus faecium 276                                                                       0.25                                                                               1     0.25                                                                               1     0.5 4     4   0.5  ≦0.06                                                                       0.5                  Enterococcus gallinarum 245                                                                   1   4     1   4     2   8     8   2    0.25                                                                               1                    Haemophilus influenzae RD                                                                     32  32    32  32    32  32    32  16   2   16                   Escherichia coli EC14                                                                         >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       206 207   208 209   210 211   212 213  214 215                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.5 8     1   1     2   1     ≦0.06                                                                       ≦0.06                                                                        1   0.5                  Staphylococcus aureus 489                                                                     1   4     0.5 1     1   0.25  ≦0.06                                                                       ≦0.06                                                                        1   2                    Staphylococcus aureus 447                                                                     0.5 8     1   1     0.5 0.5   0.25                                                                               0.25 2   0.5                  Staphylococcus aureus X400                                                                    0.5 8     0.25                                                                               1     ≦0.06                                                                       0.5   ≦0.06                                                                       ≦0.06                                                                        0.5 0.5                  Staphylococcus aureus X778                                                                    0.5 8     0.125                                                                              1     1   1     ≦0.06                                                                       ≦0.06                                                                        1   ≦0.06         Staphylococcus aureus 491                                                                     ≦0.06                                                                       1     0.5 0.25  ≦0.06                                                                       0.25  ≦0.06                                                                       ≦0.06                                                                        1   0.25                 Staphylococcus aureus S13E                                                                    1   8     0.25                                                                               0.5   ≦0.06                                                                       0.5   ≦0.06                                                                       ≦0.06                                                                        1   2                    Staphylococcus aureus SA1199                                                                  0.5 8     0.5 0.25  0.5 0.5   ≦0.06                                                                       ≦0.06                                                                        0.5 ≦0.06         Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       4     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       0.125 ≦0.06                                                                       ≦0.06                                                                        0.5 0.5                  Staphylococcus aureus SA1199B                                                                 1   16    0.5 0.5   0.125                                                                              1     ≦0.06                                                                       ≦0.06                                                                        1   1                    Staphylococcus haemolyticus 105                                                               0.5 8     0.25                                                                               0.5   1   0.5   1   0.5  1   2                    Staphylococcus haemolyticus 415                                                               1   1     2   1     1   0.5   1   2    2   1                    Staphylococcus epidermidis 270                                                                0.25                                                                               8     0.5 0.15  0.25                                                                               0.5   ≦0.06                                                                       0.5  ≦0.06                                                                       0.125                Entercoccus faecium 180                                                                       ≦0.06                                                                       1     0.25                                                                               ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       0.125                                                                               0.25                                                                               ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      0.25                                                                               0.125 ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.25                 Entercoccus faecium 276                                                                       ≦0.06                                                                       0.25  0.125                                                                              0.25  ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               2                    Enterococcus gallinarum 245                                                                   1   1     2   1     1   ≦0.06                                                                         1   2    2   64                   Haemophilus influenzae RD                                                                               32  16    >64 >64   >64 32   32  >64                  Escherichia coli EC14                                                                         >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                             ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       216 217   218 219   220 221   222 223  224 225                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   0.25  4   8     1   1         0.25 0.5 1                    Staphylococcus aureus 489                                                                     1   ≦0.06                                                                         1   8     0.5 0.25  0.125                                                                              1    0.25                                                                               2                    Staphylococcus aureus 447                                                                     1   1     1   8     0.5 0.5   0.5 0.5  0.5 1                    Staphylococcus aureus X400                                                                    1   ≦0.06                                                                         0.25                                                                               8     0.5 0.5   0.125                                                                              1    0.125                                                                              1                    Staphylococcus aureus X778                                                                    0.25                                                                               ≦0.06                                                                         1   8     0.5 0.5   ≦0.06                                                                       1    0.125                                                                              0.5                  Staphylococcus aureus 491                                                                     1   0.25  0.5 4     ≦0.06                                                                       0.125 0.125                                                                              0.125                                                                               0.125                                                                              1                    Staphylococcus aureus S13E                                                                    1   ≦0.06                                                                         32  8     0.5 0.5   ≦0.06                                                                       0.5  0.25                                                                               1                    Staphylococcus aureus SA1199                                                                  ≦0.06                                                                       ≦0.06                                                                         4   4     1   1     1   2    0.25                                                                               1                    Staphylococcus aureus SA1199A                                                                 1   ≦0.06                                                                         ≦0.06                                                                       1     ≦0.06                                                                       ≦0.06                                                                         0.125                                                                              ≦0.06                                                                        ≦0.06                                                                       0.25                 Staphylococcus aureus SA1199B                                                                 0.5 0.125 0.25                                                                               8     0.5 1     0.125                                                                              1    0.5 2                    Staphylococcus haemolyticus 105                                                               0.5 2     0.5 2     0.5 1     1   1    1   0.5                  Staphylococcus haemolyticus 415                                                               0.25                                                                               8     4   2     0.5 2     1   1    0.5 4                    Staphylococcus epidermidis 270                                                                0.125                                                                              0.5   1   4     1   0.125 0.5 0.5  0.25                                                                               1                    Entercoccus faecium 180                                                                       ≦0.06                                                                       2     ≦0.06                                                                       1     0.125                                                                              ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       1     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Entercoccus faecium 2041                                                                      0.25                                                                               ≦0.06                                                                         0.25                                                                               2     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       0.125                Entercoccus faecium 276                                                                       0.5 ≦0.06                                                                         ≦0.06                                                                       2     0.125                                                                              0.25  ≦0.06                                                                       0.125                                                                               ≦0.06                                                                       0.25                 Enterococcus gallinarum 245                                                                   64  8     ≦0.06                                                                       2     0.5 2     1   1    0.5 4                    Haemophilus influenzae RD                                                                     >64 >64   >64 32    >64 32    32  >64  32  >64                  Escherichia coli EC14                                                                         >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       226 227   228 229   230 231   232 233  234 235                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   2     4   1     0.25                                                                               0.25  4   4    4   0.5                  Staphylococcus aureus 489                                                                     0.5 2     2   1     0.25                                                                               ≦0.06                                                                         8   4    4   0.5                  Staphylococcus aureus 447                                                                     0.5 2     4   2     0.5 0.25  16  16   8   0.25                 Staphylococcus aureus X400                                                                    0.25                                                                               1     1   1     0.5 ≦0.06                                                                         8   8    8   0.125                Staphylococcus aureus X778                                                                    0.25                                                                               4     4   1     0.25                                                                               ≦0.06                                                                         8   8    4   0.5                  Staphylococcus aureus 491                                                                     0.25                                                                               2     1   0.5   0.125                                                                              ≦0.06                                                                         4   8    8   0.125                Staphylococcus aureus S13E                                                                    0.5 4     8   1     0.5 ≦0.06                                                                         8   8    8   0.125                Staphylococcus aureus SA1199                                                                  1   4     4   1     0.25                                                                               ≦0.06                                                                         16  32   8   0.25                 Staphylococcus aureus SA1199A                                                                 0.125                                                                              0.6   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         2   4    2   ≦0.06         Staphylococcus aureus SA1199B                                                                 1   4     4   1     0.25                                                                               ≦0.06                                                                         32  16   8   0.5                  Staphylococcus haemolyticus 105                                                               2   2     2   1     1   ≦0.06                                                                         2   >64  8   0.5                  Staphylococcus haemolyticus 415                                                               1   4     4   2     2   0.5   32  >64  16  1                    Staphylococcus epidermidis 270                                                                1   2     2   0.5   0.5 0.125 8   8    4   0.5                  Entercoccus faecium 180                                                                       ≦0.06                                                                       0.25  1   ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         0.5 2    1   0.5                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         1   2    1   ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.25  0.25                                                                               ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         2   2    0.5 ≦0.06         Entercoccus faecium 276                                                                       0.25                                                                               0.5   1   0.25  ≦0.06                                                                       ≦0.06                                                                         8   8    4   0.125                Enterococcus gallinarum 245                                                                   1   4     4   2     4   0.5   32  >64  16  1                    Haemophilus influenzae RD                                                                     32  >64   >64 2     32  32    16  >64  >64 8                    Escherichia coli EC14                                                                         >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                         0.125                                                                              ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06 ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       0.5  0.25                                                                               ≦0.06         __________________________________________________________________________     Organism          236 237        238 239        240 241                        __________________________________________________________________________     Staphylococcus aureus 446                                                                        1   2          1   1          1   0.5                        Staphylococcus aureus 489                                                                        4   0.5        0.5 0.5        1   0.5                        Staphylococcus aureus 447                                                                        4   1          0.5 0.5        0.5 1                          Staphylococcus aureus X400                                                                       2   1          1   0.25       0.25                                                                               0.5                        Staphylococcus aureus X778                                                                       2   0.5        0.5 0.25       0.5 1                          Staphylococcus aureus 491                                                                        4   0.25       0.25                                                                               0.25       0.25                                                                               0.25                       Staphylococcus aureus S13E                                                                       4   0.25       0.125                                                                              0.5        0.5 0.25                       Staphylococcus aureus SA1199                                                                     4   1          0.5 0.5        0.5 1                          Staphylococcus aureus SA1199A                                                                    2   ≦0.06                                                                              ≦0.06                                                                       ≦0.06                                                                              ≦0.06                                                                       ≦0.06               Staphylococcus aureus SA1199B                                                                    4   0.25       0.5 0.5        0.25                                                                               1                          Staphylococcus haemolyticus 105                                                                  4   1          0.5 1          1   1                          Staphylococcus haemolyticus 415                                                                  4   1          2   1          2   1                          Staphylococcus epidermidis 270                                                                   2   0.5        0.5 0.25       0.25                                                                               0.5                        Entercoccus faecium 180                                                                          1   0.25       0.125                                                                              ≦0.06                                                                              ≦0.06                                                                       ≦0.06               Entercoccus faecium 180-1                                                                        1   ≦0.06                                                                              ≦0.06                                                                       ≦0.06                                                                              ≦0.06                                                                       ≦0.06               Entercoccus faecium 2041                                                                         1   0.125      ≦0.06                                                                       ≦0.06                                                                              ≦0.06                                                                       ≦0.06               Entercoccus faecium 276                                                                          2   1          ≦0.06                                                                       0.25       0.5 ≦0.06               Enterococcus gallinarum 245                                                                      4   1          ≦0.06                                                                       1          2   ≦0.06               Haemophilus influenzae RD                                                                        32  8          >64 >64        >64 >64                        Escherichia coli EC14                                                                            >64 >64        >64 >64        >64 >64                        Streptococcus pyogenes C203                                                                      ≦0.06                                                                       ≦0.06                                                                              ≦0.06       ≦0.06               Streptococcus pneumoniae P1                                                                      ≦0.06                                                                       ≦0.06                                                                              ≦0.06                                                                       ≦0.06                                                                              ≦0.06                                                                       ≦0.06               __________________________________________________________________________     Organism       245 247 248 249 250  251 252  253 254  255 257                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     ≦0.06                                                                       0.5 2   64  0.25 0.25                                                                               0.125                                                                               64  32   64  ≦0.06         Staphylococcus aureus 489                                                                     ≦0.06                                                                       0.25                                                                               2   >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        16  16   >64 ≦0.06         Staphylococcus aureus 447                                                                     ≦0.06                                                                       1   4   >64 0.125                                                                               0.125                                                                              ≦0.06                                                                        16  16   >64 0.25                 Staphylococcus aureus X400                                                                    ≦0.06                                                                       0.5 4   >64 ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               32  8    >64 ≦0.06         Staphylococcus aureus X778                                                                    ≦0.06                                                                       0.5 4   >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        16  4    >64 ≦0.06         Staphylococcus aureus 491                                                                     0.5 0.5 1   32  ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        2   1    >64 ≦0.06         Staphylococcus aureus S13E                                                                        0.5 0.5 >64 ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               32  32   >64 ≦0.06         Staphylococcus aureus SA1199                                                                  0.25                                                                               1   1   >64 ≦0.06                                                                        ≦0.06                                                                       0.125                                                                               32  8    >64 ≦0.06         Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                       1   8   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        1   0.5  16  ≦0.06         Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       0.5 8   >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        32  16   >64 ≦0.06         Staphylococcus haemolyticus 105                                                               1   1   2   >64 2    2   0.5  16  16   >64 2                    Staphylococcus haemolyticus 415                                                               8   2   4   >64 4    4   1    16  16   >64 8                    Staphylococcus epidermidis 270                                                                0.5 1   0.5 32  0.25 0.25                                                                               0.125                                                                               8   8    >64 0.25                 Entercoccus faecium 180                                                                       2   0.5 0.25                                                                               16  2    2   0.5  0.5 0.25 >64 4                    Entercoccus faecium 180-1                                                                     ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       4   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.5 0.25 16  ≦0.06         Entercoccus faecium 2041                                                                      ≦0.06                                                                       0.125                                                                              1   >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        4   4    16  ≦0.06         Entercoccus faecium 276                                                                       ≦0.06                                                                       0.25                                                                               2   >64 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        16  8    >64 ≦0.06         Enterococcus gallinarum 245                                                                   ≦0.06                                                                       0.125                                                                              4   >64 4    4   1    16  16   >64 ≦0.06         Haemophilus influenzae RD                                                                     >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Escherichia coli EC14                                                                         0.5 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   2   ≦0.06                                                                       ≦0.06                                                                       0.5 ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               0.5  16  ≦0.06         Streptococcus pneumoniae P1                                                                   1   ≦0.06                                                                       ≦0.06                                                                       1   ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06                                                                        1   ≦0.06         __________________________________________________________________________     Organism       258 260 262 263 265  266 267  268 269  270 271                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     1   2   2   1   2    4   0.5  2   2    1   1                    Staphylococcus aureus 489                                                                     1   2   1   0.25                                                                               0.5  4   0.25 1   0.25 0.25                                                                               1                    Staphylococcus aureus 447                                                                     1   4   1   2   2    4   0.5  4   4    0.5 2                    Staphylococcus aureus X400                                                                    2   4   2   0.5 0.5  4   0.5  2   0.5  1   2                    Staphylococcus aureus X778                                                                    1   1   1   0.5 0.5  2   1    2   0.25 0.5 0.5                  Staphylococcus aureus 491                                                                     1   1   1   1   2    2   1    1   1    0.25                                                                               0.5                  Staphylococcus aureus S13E                                                                    2   4   1   1   0.5  4   1    4   1    2   1                    Staphylococcus aureus SA1199                                                                  2   2   0.5 1   2    4   2    4   0.25 1   2                    Staphylococcus aureus SA1199A                                                                 2   0.5 ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.5 ≦0.06                                                                        0.5 ≦0.06                                                                        ≦0.06                                                                       0.5                  Staphylococcus aureus SA1199B                                                                 0.25                                                                               2   0.5 1   0.5  2   1    2   0.5  2   1                    Staphylococcus haemolyticus 105                                                               1   1   4   16  8    16  16   8   8    4   2                    Staphylococcus haemolyticus 415                                                               2   2   2   8   1    8   4    4   4    2   2                    Staphylococcus epidermidis 270                                                                2   1   1   4   4    2   4    1   8    1   1                    Entercoccus faecium 180                                                                       1   0.5 1   ≦0.06                                                                       8    2   0.25 0.5 4    0.25                                                                               2                    Entercoccus faecium 180-1                                                                     4   0.25                                                                               ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        0.5 0.125                                                                               0.25                                                                               0.125                                                                               ≦0.06                                                                       0.125                Entercoccus faecium 2041                                                                      0.5 1   0.5 ≦0.06                                                                       0.25 2   0.25 1   0.125                                                                               0.5 2                    Entercoccus faecium 276                                                                       1   2   2   0.5 0.5  2   1    2   0.125                                                                               1   1                    Enterococcus gallinarum 245                                                                   1   0.25                                                                               2   8   1    8   4    4   4    2   2                    Haemophilus influenzae RD                                                                     >64 >64 >64 >64 >64  >64 >64  >64 >64  >64 >64                  Escherichia coli EC14                                                                         >64 >64 >64 65  >64  >64 >64  >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06                                                                        ≦0.06                                                                       ≦0.06         __________________________________________________________________________     Organism       272 273   274 275   276 277   278 279  280 281                  __________________________________________________________________________     Staphylococcus aureus 446                                                                     0.25                                                                               2     8   0.25  1   64    1   0.5  2   64                   Staphylococcus aureus 489                                                                     0.125                                                                              2     2   ≦0.06                                                                         1   16    0.5 0.125                                                                               1   32                   Staphylococcus aureus 447                                                                     0.25                                                                               4     16  1     4   >64   2   1    8   >64                  Staphylococcus aureus X400                                                                    0.125                                                                              2     8   0.25  2   32    0.25                                                                               0.25 1   >64                  Staphylococcus aureus X778                                                                    0.125                                                                              2     4   ≦0.06                                                                         1   32    0.5 0.25 0.5 16                   Staphylococcus aureus 491                                                                     0.25                                                                               4     4   1     1   8     1   0.25 2   >64                  Staphylococcus aureus S13E                                                                    0.125                                                                              4     4   0.125 2   16    1   0.25 2   32                   Staphylococcus aureus SA1199                                                                  0.25                                                                               4     2   ≦0.06                                                                         1   16    0.25                                                                               0.5  2   >64                  Staphylococcus aureus SA1199A                                                                 ≦0.06                                                                       ≦0.06                                                                         1   ≦0.06                                                                         0.25                                                                               1     1   ≦0.06                                                                        0.5 4                    Staphylococcus aureus SA1199B                                                                 ≦0.06                                                                       2     2   0.125 1   16    0.5 ≦0.06                                                                        0.5 32                   Staphylococcus haemolyticus 105                                                               0.125                                                                              4     >64 1     4   >64   0.5 4    >64 >64                  Staphylococcus haemolyticus 415                                                               0.5 8     >64 4     4   >64   2   2    32  >64                  Staphylococcus epidermidis 270                                                                ≦0.06                                                                       2     16  1     4   16    1   1    8   >64                  Entercoccus faecium 180                                                                       0.5 2     >64 1     4   2     1   ≦0.06                                                                        32  >64                  Entercoccus faecium 180-1                                                                     ≦0.06                                                                       0.25  0.5 ≦0.06                                                                         0.25                                                                               0.5   ≦0.06                                                                       ≦0.06                                                                        0.25                                                                               4                    Entercoccus faecium 2041                                                                      0.125                                                                              0.5   1   ≦0.06                                                                         1   2     0.125                                                                              ≦0.06                                                                        1   8                    Entercoccus faecium 276                                                                       0.125                                                                              2     1   ≦0.06                                                                         1   1     0.25                                                                               0.125                                                                               0.5 8                    Enterococcus gallinarum 245                                                                   0.5 8     >64 4     4   >64   2   2    32  >64                  Haemophilus influenzae RD                                                                     >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Escherichia coli EC14                                                                         >64 >64   >64 >64   >64 >64   >64 >64  >64 >64                  Streptococcus pyogenes C203                                                                   ≦0.06                                                                       ≦0.06                                                                         0.125                                                                              ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              0.5                  Streptococcus pneumoniae P1                                                                   ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                         ≦0.06                                                                       ≦0.06                                                                        0.125                                                                              ≦0.06         __________________________________________________________________________     Organism       282      283 284      285 286      287 288                      __________________________________________________________________________     Staphylococcus aureus 446                                                                     32       16  8        4   1        1   2                        Staphylococcus aureus 489                                                                     8        8   2        1   2        0.5 2                        Staphylococcus aureus 447                                                                     >64      32  8        32  8        4   2                        Staphylococcus aureus X400                                                                    16       16  4        4   2        0.5 2                        Staphylococcus aureus X778                                                                    16       8   1        1   4        0.5 2                        Staphylococcus aureus 491                                                                     16       4   2        4   2        1   2                        Staphylococcus aureus S13E                                                                    16       4   4        1   4        1   2                        Staphylococcus aureus SA1199                                                                  16       32  8        2   2        0.5 2                        Staphylococcus aureus SA1199A                                                                 1        4   0.25     0.25                                                                               ≦0.06                                                                            ≦0.06                                                                       1                        Staphylococcus aureus SA1199B                                                                 16       32  4        1   4        0.25                                                                               1                        Staphylococcus haemolyticus 105                                                               >64      >64 32       16  8        8   2                        Staphylococcus haemolyticus 415                                                               >64      32  32       16  4        16  4                        Staphylococcus epidermidis 270                                                                >64      16  16       8   4        4   1                        Entercoccus faecium 180                                                                       32       4   8        16  8        16  4                        Entercoccus faecium 180-1                                                                     1        0.125                                                                              0.5      0.25                                                                               0.25     0.125                                                                              1                        Entercoccus faecium 2041                                                                      4        2   1        0.5 1        0.125                                                                              1                        Entercoccus faecium 276                                                                       4        16  8        0.5 1        0.25                                                                               2                        Enterococcus gallinarum 245                                                                   >64      32  32       16  4        0.5 2                        Haemophilus influenzae RD                                                                     >64      >64 >64      >64 >64      >64 >64                      Escherichia coli EC14                                                                         >64      >64 >64      >64 >64      >64 >64                      Streptococcus pyogenes C203                                                                   ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06             Streptococcus pneumoniae P1                                                                   ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06                                                                            ≦0.06                                                                       ≦0.06             __________________________________________________________________________

The formula I compounds have also shown in vivo antimicrobial activity against experimentally-induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with the test organism, the activity observed was measured as an ED5O value (effective dose in mg/kg to protect 50% of the test animals: see W. Wick et al., J. Bacteriol. 81, 233-235 (1961)). ED₅₀ values observed for illustrative compounds are given in Table 4.

                  TABLE 4                                                          ______________________________________                                         In Vivo Activity of Formula I Compounds ED50                                   (mg/kg/2)                                                                              Stapylococcus                                                                               Streptococcus                                                                             Streptococcus                                  Compound                                                                               aureus       pyogenes   pneumoniae                                     ______________________________________                                         vancomycin                                                                             1.2          0.8        1.1                                            A82846A 0.19         0.084      0.39                                           A82846B 0.25         0.12       0.18                                           A82846C 1.3          1.5        4.6                                             1      0.086        0.052      0.025                                           2      0.27         0.014      0.025                                           4      0.36         0.012      0.036                                           5      0.13         0.039      0.036                                           6      0.15         0.013      0.021                                           8      0.12         >0.5       0.273                                           12     0.13         >0.5       >0.5                                            14     0.43         0.37       >0.5                                            22     0.049        >0.5       >.05                                            25     0.16         0.087      0.088                                           29     0.088        0.1        0.054                                           32     0.055        0.034      0.039                                           36     0.19         0.28       0.31                                            39     0.1          0.045      <0.031                                          41     n.d.         0.082      0.087                                           46     n.d.         0.378      0.156                                           49     0.053        0.045      <0.031                                          50     0.1          0.047      0.057                                           51     0.16         0.057      0.036                                           52     0.052        0.046      0.074                                           53     0.077        0.16       0.071                                           57     0.041        0.054      0.046                                           64     n.d.         0.044      <0.031                                          87     n.d.         0.054      0.027                                           90     n.d.         0.058      0.049                                           93     n.d.         0.074      0.012                                           94     n.d.         0.16       0.049                                           97     n.d.         0.066      0.038                                          100     n.d.         0.062      0.046                                          104     n.d.         0.12       0.041                                          105     n.d.         0.12       0.041                                          106     n.d.         0.2        0.036                                          107     n.d.         0.27       0.092                                          108     n.d.         0.046      0.041                                          111     n.d.         0.099      0.084                                          114     n.d.         0.091      0.76                                           116     n.d.         0.89       0.058                                          118     n.d.         0.91       0.046                                          119     n.d.         0.16       0.08                                           120     n.d.         0.058      0.005                                          121     n.d.         0.041      0.047                                          122     n.d.         0.23       0.31                                           123     n.d.         0.076      0.039                                          124     n.d.         0.092      0.041                                          131     n.d.         <0.031     0.077                                          204     n.d.         <0.031     0.046                                          211     n.d.         <0.031     0.041                                          223     n.d.         <0.031     <0.031                                         229     n.d.         0.058      0.078                                          230     n.d.         0.046      0.078                                          ______________________________________                                          n.d. = not done                                                          

One important aspect of the antimicrobial activity of many of the formula I compounds is their activity against vancomycin-resistant enterococci. This activity is illustrated in Table 5, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant and vancomycin-susceptible enterococci (Enterococcus faecium and Enterococcus faecalis, mean geometric MIC (mcg/mL)), as determined using the standard broth micro-dilution assay. End points were read after 24-hour incubation. Modification of the amino sugar of the disaccharide moiety provides improved activity against vancomycin-resistant strains over the parent glycopeptide antibiotic.

                  TABLE 5                                                          ______________________________________                                                       Vancomycin                                                                               Vancomycin                                             Compound      Resistant Sensitive                                              No.           Strains   Strains                                                ______________________________________                                         vancomycin    282       3.9                                                    A82846A       >64       1.7                                                    A82846B       29        0.22                                                   A82846C       353       1.3                                                     1            0.25      0.0061                                                  2            0.044     0.00038                                                 3            2.8       0.11                                                    4            0.50      0.062                                                   5            0.50      0.072                                                   6            1.2       0.14                                                    7            2.8       0.43                                                    8            1.0       0.57                                                    9            11        0.38                                                    10           3.4       3.5                                                     11           6.7       0.22                                                    12           1.7       1.1                                                     13           19        0.76                                                    14           0.50      0.76                                                    15           6.7       0.14                                                    16           9.5       0.67                                                    17           9.5       0.38                                                    18           6.7       0.38                                                    19           4.8       0.22                                                    20           4.8       0.38                                                    21           5.7       4.3                                                     22           1.0       1.5                                                     23           5.7       2.0                                                     24           54        0.67                                                    25           4.0       0.22                                                    26           54        0.66                                                    27           45        1.5                                                     28           4.7       0.71                                                    29           0.21      0.031                                                   30           4.7       0.071                                                   31           9.5       1.2                                                     32           0.50      0.089                                                   33           2.8       0.18                                                    34           4.0       3.4                                                     35           5.6       0.25                                                    36           0.25      0.21                                                    37           2.4       0.25                                                    38           4.0       0.42                                                    39           1.2       0.09                                                    40           0.50      0.31                                                    41           0.84      0.21                                                    42           1.7       0.089                                                   43           13        1.1                                                     44           13        0.50                                                    45           2.0       0.50                                                    46           0.71      0.50                                                    47           4.7       0.57                                                    48           4.8       0.50                                                    49           0.71      0.083                                                   50           0.12      0.054                                                   51           0.84      0.22                                                    52           0.59      0.11                                                    53           0.35      0.25                                                    54           1.7       0.56                                                    55           13        1.7                                                     56           19        1.0                                                     57           0.35      0.041                                                   58           5.7       0.76                                                    59           51        0.42                                                    60           19        3.0                                                     61           16        0.65                                                    62           9.5       0.22                                                    63           54        0.66                                                    64           0.71      0.077                                                   65           2.4       0.20                                                    66           16        0.76                                                    67           1.7       0.16                                                    68           6.7       0.25                                                    69           13        0.44                                                    70           2.0       0.092                                                   71           11        0.57                                                    72           4.7       0.28                                                    73           11        0.25                                                    74           11        0.33                                                    75           16        0.50                                                    76           8.0       0.29                                                    78           16        0.76                                                    79           0.84      0.042                                                   80           1.7       0.25                                                    81           1.0       0.042                                                   82           22        0.50                                                    83           54        1.7                                                     84           23        0.66                                                    85           3.4       0.11                                                    86           1.4       0.036                                                   87           0.71      0.047                                                   88           1.7       0.055                                                   89           11        0.44                                                    90           0.71      0.041                                                   91           2.8       0.11                                                    92           1.7       0.082                                                   93           0.42      0.042                                                   94           0.50      0.041                                                   95           1.7       0.054                                                   96           1.4       0.11                                                    97           0.71      0.054                                                   98           2.4       0.095                                                   99           72        0.76                                                   100           0.71      0.042                                                  101           4.0       0.25                                                   102           2.0       0.13                                                   103           4.0       0.33                                                   104           1.2       0.062                                                  105           0.84      0.062                                                  106           0.71      0.034                                                  107           0.59      0.082                                                  108           0.84      0.04                                                   109           72        0.22                                                   110           1.7       0.047                                                  111           0.71      0.031                                                  112           1.4       0.072                                                  113           0.84      0.054                                                  114           0.59      0.031                                                  115           8.0       0.19                                                   116           0.42      0.031                                                  117           4.8       0.14                                                   118           0.84      0.048                                                  119           0.59      0.048                                                  120           1.0       0.072                                                  121           1.0       0.063                                                  122           1.0       0.054                                                  123           1.0       0.041                                                  124           0.84      0.047                                                  125           3.4       0.14                                                   126           2.4       0.11                                                   127           1.2       0.33                                                   128           2.0       0.11                                                   129           27        1.52                                                   130           4.8       0.22                                                   131           0.84      0.028                                                  132           1.2       0.048                                                  133           4.0       0.13                                                   134           2.0       0.13                                                   135           4.8       0.22                                                   136           23        0.76                                                   137           6.7       0.38                                                   138           38        0.87                                                   139           23        0.38                                                   140           6.7       0.19                                                   141           8.0       0.25                                                   142           45        1.5                                                    143           2.0       0.048                                                  144           11        9.2                                                    145           64        1.3                                                    146           64        1.5                                                    147           25        1.3                                                    148           0.15      0.052                                                  149           45        0.66                                                   150           1.7       0.25                                                   151           4.5       0.14                                                   152           27        1.2                                                    153           1.4       0.083                                                  154           2.8       0.072                                                  155           128       1.3                                                    156           5.7       0.17                                                   157           2.0       0.054                                                  158           1.7       1.0                                                    159           27        0.50                                                   160           9.5       0.22                                                   161           23        0.44                                                   162           4.8       0.12                                                   163           2.0       0.87                                                   164           1.7       0.11                                                   165           4.0       0.062                                                  166           1.7       0.055                                                  167           1.0       0.055                                                  168           3.4       0.10                                                   169           19        0.50                                                   170           8.0       0.22                                                   171           9.5       0.22                                                   172           3.4       0.13                                                   173           2.0       0.12                                                   174           19        0.76                                                   175           9.5       0.22                                                   176           1.2       0.13                                                   178           2.8       0.13                                                   179           1.7       0.060                                                  180           >128      0.71                                                   181           8.0       0.060                                                  182           13        0.250                                                  183           23        0.130                                                  184           27        0.570                                                  185           4.7       0.060                                                  186           11        0.290                                                  189           2.4       0.10                                                   190           6.7       0.29                                                   191           6.7       0.57                                                   192           0.84      0.035                                                  193           2         0.072                                                  194           2.4       0.083                                                  195           2.0       0.042                                                  196           1.7       0.027                                                  197           1.2       0.16                                                   198           3.4       0.062                                                  199           1.4       0.036                                                  200           1.4       0.041                                                  201           1.2       0.44                                                   202           1.4       0.76                                                   203           1.0       0.036                                                  204           0.71      0.031                                                  205           1         0.036                                                  206           1.7       0.095                                                  207           1.2       0.50                                                   208           2.8       0.17                                                   209           1.2       0.136                                                  210           0.84      0.041                                                  211           0.35      0.024                                                  212           0.50      0.036                                                  213           1.0       0.55                                                   214           0.71      0.024                                                  215           2.8       0.25                                                   216           0.35      0.032                                                  217           13        0.57                                                   218           1.0       0.11                                                   219           0.71      0.044                                                  220           0.71      0.05                                                   221           0.71      0.041                                                  222           0.84      0.072                                                  223           0.79      0.055                                                  224           0.63      0.055                                                  225           0.63      0.072                                                  226           1.6       0.041                                                  227           0.71      0.11                                                   228           1.0       0.14                                                   229           0.50      0.024                                                  230           0.35      0.031                                                  231           1.7       0.11                                                   232           0.71      0.29                                                   233           1.7       1.7                                                    234           2         2                                                      235           2.4       0.25                                                   236           1.4       0.5                                                    237           1.0       0.048                                                  238           1.4       0.14                                                   239           2.8       0.095                                                  240           1.19      0.055                                                  241           1.4       0.048                                                  245           13        0.38                                                   246           8         4                                                      247           2.4       0.29                                                   248           2         0.66                                                   249           11        3.5                                                    250           16        0.44                                                   251           2         0.66                                                   252           9.5       0.1                                                    253           4.8       3                                                      254           2         0.5                                                    255           64        32                                                     257           64        1                                                      258           8         1                                                      260           4.8       1.1                                                    261           >128      4.59                                                   262           5.7       0.17                                                   263           1.7       0.29                                                   265           54        0.87                                                   266           11        2.3                                                    267           2.8       0.22                                                   268           6.7       0.87                                                   269           38        1.1                                                    270           2.8       0.66                                                   271           5.7       0.33                                                   272           4.75      0.072                                                  273           2.8       0.38                                                   274           >128      9.2                                                    275           16        0.33                                                   276           23        1.3                                                    277           32        1.1                                                    278           8         0.29                                                   279           2.4       0.11                                                   280           >128      7                                                      281           >128      37                                                     282           45        2.6                                                    283           32        1.7                                                    284           38        2.3                                                    285           90        2.4                                                    286           19        1.1                                                    287           45        1.1                                                    288           11        1.7                                                    ______________________________________                                    

A number of the lactic acid bacteria including all Leuconostocs, all Pediococci, and some Lactobacilli, are intrinsically resistant to vancomycin. With the increased use of vancomycin, infections due to these bacteria have been reported with increasing frequency in immunocompromised patients (Handwerger et al., Reviews of Infectious Disease 12:602-610 (1990); Ruoff et al., Journal of Clinical Microbiology 26:2064-2068 (1988)). One important aspect of the antimicrobial activity of the formula I compounds is their activity against the vancomycin-resistant lactic acid bacteria. The compounds of the present are useful in inhibiting the growth of vancomycin-resistant lactic bacteria such as Leuconostoc, Pedicocci, and Lactobacilli and thus, controlling opportunistic infections by this group of bacteria. This activity is illustrated in Table 6, which summarizes a comparison of the activity of illustrative compounds against representative vancomycin-resistant lactic acid bacteria (Pedicoccus acidilacti Pedicoccus pentosaceus, Leuconostoc lactis, Leuconostoc mesenteroides, Leuconostoc pseudomesenteroides, Leuconostoc citreum, and Lactobacillus confusus, mean geometric MIC (mcg/mL)), as determined using a standard agar dilution assay on brain-heart infusion agar.

                                      TABLE 6                                      __________________________________________________________________________     In Vitro Activity of Formula I Compounds                                       MIC (mcg/ml)/Compound                                                          Pediococcus Pediococcus                                                                          Leuconostoc                                                                          Leuconostoc                                                                           Leuconostoc                                     acidilacti  pentosaceus                                                                          lactis                                                                               mesenteroides                                                                         pseudomesent-                                                                         Leuconostoc                                                                          Lactobacillus                      (mean of 10)                                                                               (mean of 2)                                                                          (mean of 2)                                                                          (mean of 4)                                                                           eroides                                                                               citreum                                                                              confusus                           __________________________________________________________________________     Vancomycin                                                                           891   1024  1024  1024   >1024  >1024 1024                               A82846B                                                                              141   >256  64    >256   >256   >256  >256                                1    18    23    23    64     >128   >128  64                                  2    5.9   11    4.0   16     32     64    16                                  4    7.5   16    16    16     32     128   32                                  5    2.8   8.0   8.0   8      16     64    16                                  6    4.3   8.0   8.0   9.5    16     64    16                                 14    3.7   5.7   8.0   11     32     64    32                                 29    4.0   8.0   5.7   6.7    16     32    8                                  32    12.1  16    16    16     32     64    16                                 36    9.2   16    16    16     32     32    32                                 39    26    32    32    32     64     >64   32                                 41    71    91    91    91     >128   >128  64                                 49    55    64    64    64     128    128   64                                 50    51    64    64    64     128    128   64                                 51    87    91    64    76     >128   >128  64                                 52    55    64    64    76     64     >128  64                                 58    55    64    64    64     128    128   64                                 108   12    23    8.0   10     32     64    16                                 118   16    16    11    13     32     64    16                                 122   24    16    16    16     32     64    16                                 124   20    16    16    16     64     64    16                                 __________________________________________________________________________

Pharmaceutical formulations of the formula I compounds are also part of this invention. Thus, the compound, preferably in the form of a pharmaceutically acceptable salt, can be formulated for oral or parenteral administration for the therapeutic or prophylactic treatment of bacterial infections.

For example, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. The compositions comprising a formula I compound will contain from about 0.1 to about 90% by weight of the active compound, and more generally from about 10 to about 30%. The compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid.

Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.

Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used.

It may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.

For intravenous (IV) use, a water soluble form of the antibiotic can be dissolved in one of the commonly used intravenous fluids and administered by infusion. Such fluids as, for example, physiological saline, Ringer's solution, or 5% dextrose solution can be used.

For intramuscular preparations, a sterile formulation of a suitable soluble salt form of the compound, for example the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as pyrogen-free water (distilled), physiological saline or 5% glucose solution. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, for example, an ester of a long chain fatty acid such as ethyl oleate.

For oral use, a sterile formulation of a suitable salt form of the antibiotic, for example, the hydrochloride salt, formulated in a diluent such as distilled or deionized water, is particularly useful.

Alternatively, the unit dosage form of the antibiotic can be a solution of the antibiotic, preferably in its salt form, in a suitable diluent in sterile, hermetically sealed ampoules. The concentration of the antibiotic in the unit dosage may vary, for example, from about 1 percent to about 50 percent depending on the particular form of the antibiotic and its solubility and the dose desired by the physician.

In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive microorganisms, in animals. The compounds of this invention are particularly useful in treating infections caused by methicillin-resistant staphylococci. Also, the compounds are useful in treating infection due to enterococci. Examples of such diseases are severe staphylococcal infections, for example, staphylococcal endocarditis and staphylococcal septicemia. The animal may be either susceptible to, or infected with, the microorganism. The method comprises administering to the animal an amount of a formula I compound which is effective for this purpose. In general, an effective amount of a formula I compound is a dose between about 0.5 and about 100 mg/kg. A preferred dose is from about 1 to about 60 mg/kg of active compound. A typical daily dose for an adult human is from about 50 mg to about 5 g.

In practicing this method, the antibiotic can be administered in a single daily dose or in multiple doses per day. The treatment regimen may require administration over extended periods of time, for example, for several days or for from one to six weeks. The amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the antibiotic and the microorganism or microorganisms involved in the infection.

A convenient method of practicing the treatment method is to administer the antibiotic via intravenous infusion. In this procedure a sterile formulation of a suitable soluble salt of the antibiotic is incorporated in a physiological fluid, such as 5% dextrose solution, and the resulting solution is infused slowly IV. Alternatively, the piggy-back method of IV infusion can also be used.

In order to illustrate more fully the operation of this invention, the following examples are provided, but are not to be construed as a limitation on the scope of the invention.

EXAMPLE 1 METHOD A

Preparation of Compound 2

A mixture of A82846B·triacetate, (2.25 g, 1.27 mmol, 1.0 equivalents (eq)) in 1:1 DMF/methanol (140 mL) under an atmosphere of argon was treated with 4-biphenylcarboxaldehyde (331 mg, 2.12 mmol, 1.7 eq). The resulting mixture was heated to 70° C. and maintained as such for 1.75-2 hours. The solution was then treated with sodium cyanoborohydride (554 mg, 8.83 mmol, 6.9 eq) . Heating at 70° C. was continued for an additional 1.75-2 hours after which the reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water (150 mL), and lyophilized to give a solid.

The solid was purified by preparative reverse-phase high performance liquid chromatography (HPLC) using a Waters 3×(40×100 mm) C₁₈ Nova-Pak cartridge with Waters C₁₈ Nova-pak guard insert and utilizing TEAP buffer system. The analytical method for analysis was: 0.2% TEA/phosphoric acid (TEAP), pH=3, the gradient system at time 0 was 5% CH₃ CN/94.8% H₂ O with 0.2% TEAP held constant and at 20 minutes was 60% CH₃ CN/39.8% H₂ O with 0.2% TEAP held constant. The UV wavelength used was 235 nm and the flow rate was 2 ml/minute. Analysis was done using a Waters Nova-pak C₁₈ RCM column (8×100mm) with a Nova-pak C₁₈ guard insert. It is necessary to desalt the product after reverse phase purification when this HPLC method is used.

Desalting was accomplished by adding the purified product to 5-10 ml of H₂ O. 1N HCl was added dropwise with stirring to dissolve the sample. The pH at this point was approximately 1-3. The pH of the solution was then raised to 8.2 with 1N NaOH. A white solid precipitated out of solution. The mixture was cooled, filtered, and dried under vacuum at room temperature for 8-15 hours to give the zwitter ion (or neutral compound) of the desired product, compound 2 (p-phenylbenzyl·A82846B), (1.02 g, 45%).

EXAMPLE 2

Preparation of Compound 4

A mixture of A82846B·triacetate (1.5 g, 0.848 mmol, 1.0 eq) in methanol (100 mL) under an atmosphere of argon was treated with p-phenoxybenzaldehyde (298 mg, 1.51 mmol, 1.8 eq). The resulting mixture was heated to reflux and maintained as such for 2 hours. The solution was then treated with sodium cyanoborohydride (326 mg, 5.18 mmol, 6.1 eq). Heating at reflux was continued for an additional 2 hours after which the reaction mixture was cooled to room temperature and evaporated to dryness in vacuo.

The product was purified by reverse-phase HPLC with a TFA buffer. The analytical method for analysis was accomplished by using a Waters Nova-pak C₁₈ RCM column (8×100 mm) with a Nova-pak C₁₈ guard insert, eluting with a 2.0 ml/minute linear gradient of 15% acetonitrile/0.1% TFA at time zero to 80% acetonitrile/0.1% TFA at 15 minutes. The fractions containing the products were detected by ultraviolet scan at 235 nm. The organic solvent of the desired fractions was removed and the mixture was lyophilized to a white solid to give 0.618 mg of p-phenoxybenzyl·A82846B compound 4·tris(trifluoroacetate) salt (20% yield). No desalting or further purification was necessary. This method is also especially useful in the preparation of Compound 2 wherein phenylbenzaldehyde is one of the starting materials.

EXAMPLE 3 Method B

Preparation of Compound 176

A mixture of A82846B·triacetate (280 mg, 0.157 mmol, 1.0 eq) in 1:1 DMF/methanol (30 mL) was treated with 8-phenyloctanal (59 mg, 0.29 mmol, 1.8 eq) and sodium cyanoborohydride (60 mg, 0.95 mmol, 6.1 eq). The resulting mixture was heated, under an atmosphere of nitrogen, to 70° C. and maintained as such for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give a residue. Purification of the product was accomplished by reverse-phase preparative HPLC utilizing a Waters 2×(40×100 mm) C₁₈ Nova-Pak cartridge with Waters C₁₈ Nova-Pak guard insert. Elution was accomplished with a 30 minute linear gradient (time=0 minutes 95% TEAP (0.5% aqueous triethylamine adjusted to pH=3 with phosphoric acid)/5% CH₃ CN to t=30 minutes 20% TEAP/80% CH₃ CN) with a flow rate of 40 mL/minute and UV detection at 280 nm. The desired fraction was concentrated in vacuo then desalted with a Waters Sep-Pak cartridge as described below. This afforded compound 176 in 22% yield (60 mg).

The resulting compound was desalted as follows. A Waters Sep-Pak cartridge was pre-wet with methanol (2-3 column volumes) then conditioned with water (2-3 column volumes). The sample, dissolved in a minimum volume of water, was loaded onto the Sep-Pak column which was then washed with water (2-3 column volumes) to remove the unwanted salts. The product was then eluted with an appropriate solvent system, typically 1:1 CH₃ CN/H₂ O, CH₃ CN, and/or methanol. The organic solvent component was removed in vacuo and the resulting aqueous solution lyophilized to give the final product.

EXAMPLE 4

Preparation of Compound 229

A three liter 3-necked flask was fitted with a condenser, nitrogen inlet and overhead mechanical stirring apparatus. The flask was charged with pulverized A82846B acetate salt (20.0 g, 1.21×10⁻³ mol) and methanol (1000 mL) under a nitrogen atmosphere. 4'-chlorobiphenylcarboxaldehyde (2.88 g, 1.33×10⁻² mol, 1.1 eq.) was added to this stirred mixture, followed by methanol (500 mL). Finally, sodium cyanoborohydride (0.84 g, 1.33×10⁻² mol, 1.1 eq.) was added followed by methanol (500 mL). The resulting mixture was heated to reflux (about 65° C.).

After 1 hour at reflux, the reaction mixture attained homogeneity. After 25 hours at reflux, the heat source was removed and the clear reaction mixture was measured with a pH meter (6.97 at 58.0° C.). 1N NaOH (22.8 mL) was added dropwise to adjust the pH to 9.0 (at 54.7° C.). The flask was equipped with a distillation head and the mixture was concentrated under partial vacuum to a weight of 322.3 grams while maintaining the pot temperature between 40°-45° C.

The distillation head was replaced with an addition funnel containing 500 mL of isopropanol (IPA). The IPA was added dropwise to the room temperature solution over 1 hour. After approximately 1/3 of the IPA was added, a granular precipitate formed. The remaining IPA was added at a faster rate after precipitation had commenced. The flask was weighed and found to hold 714.4 grams of the IPA/methanol slurry.

The flask was re-equipped with a still-head and distilled under partial vacuum to remove the remaining methanol. The resulting slurry (377.8 g) was allowed to chill in the freezer overnight. The crude product was filtered through a polypropylene pad and rinsed twice with 25 mL of cold IPA. After pulling dry on the funnel for 5 minutes, the material was placed in the vacuum oven to dry at 40° C. A light pink solid (22.87 g (theory=22.43 g)) was recovered. HPLC analysis versus a standard indicated 68.0% weight percent of Compound 229 (4- 4-chlorophenyl!benzyl-A82846B! in the crude solid, which translated into a corrected crude yield of 69.3%.

The products of the reaction were analyzed by reverse-phase HPLC utilizing a Zorbax SB-C₁₈ column with ultraviolet light (UV; 230 nm) detection. A 20 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minutes to 40% aqueous buffer/60% CH₃ CN at time=20 minutes was used, where the aqueous buffer was TEAP (5 ml CH₃ CN, 3 ml phosphoric acid in 1000 ml water).

EXAMPLE 5

Preparation of Compound 252, 253, 254, 255

The following procedure is referred to herein as Method D. A 100 ml 3 necked flask was fitted with a condenser and charged with 0.75 g (0.45 mmol) of A82846B, 0.197 g (2 eqs., 0.91 mmol) of 4'-chloro-biphenylcarboxaldehyde, 0.086 g (3 eqs., 1.4 mmol) sodium cyanoborohydride, 25 ml methanol and 25 ml H₂ O. The mixture was heated to reflux and monitored by HPLC. After 6.5 hours, heating was stopped and the mixture transferred to a single-neck recovery flask. Concentration in vacuo afforded 1.02 g of off-white solids. This material was subjected to preparative chromatography for isolation of the desired components.

The products of the reaction were analyzed by reverse-phase HPLC utilizing a Zorbax SB-C₁₈ column with ultraviolet light (UV; 230 nm) detection. A 20 minute gradient solvent system consisting of 95% aqueous buffer/5% CH₃ CN at time=0 minutes to 40% aqueous buffer/60% CH₃ CN at time=20 minutes was used, where the aqueous buffer was TEAP (5 ml CH₃ CN, 3 ml phosphoric acid in 1000 ml water). The resulting material was held for five minutes and then returned to 95% aqueous buffer/5% CH₃ CN. The reaction yielded 9.19% starting material (A82846B), 14.93% Compound 229, 21.22% Compound 252, 10.53% Compound 253, 25.89% Compound 254, and 4.99% Compound 255.

In order to enrich for the formation of compounds 253, and 255, the following procedure, which is referred to herein as Method E, was utilized. A 100 ml 3 necked flask was fitted with a condenser and nitrogen inlet. The flask was charged with 1 q (0.61 mmol) of A82846B, 0.394 g (3 eqs., 1.82 mmol) of 4'-chloro-biphenylcarboxaldehyde, 0.114 g (3 eqs., 1.82 mmol) sodium cyanoborohydride and 50 ml methanol). The mixture was heated to reflux and allowed to stir under nitrogen overnight. After 25 hours at reflux, heating was stopped and the mixture was transferred to a single-neck recovery flask and concentrated in vacuo. 1.42 g of off-white solids were recovered. Using the analytical HPLC method described above in this Example it was determined that the reaction yielded 5.19% of Compound 229, 25.14% of Compound 253, 10.15% of Compound 254, and 42.37% of Compound 255.

Preparative chromatography was used to isolate Compounds 252, 253, 254, 255. A 200 mg aliquot of either the preparation from Method D or E, above, was dissolved in 2.5 ml of 1:1 AcOH:methanol and injected into a Waters Prep 3000 preparative chromatography unit with a Waters Nova-Pak C-18 reverse phase column (3×40mm×100mm) using ultraviolet light (UV; 235 nm) detection. A 45 minute gradient solvent system consisting of 15% acetonitrile/75% water/10% of a 1% TFA aqueous buffer at time=0 minutes to 85% acetonitrile/15% water/10% of a 1% TFA aqueous buffer at time=45 minutes was used with a flow rate of 40 ml/min. Elution of the material was observed via a strip chart recorder. Fractions were collected. All fractions containing Compound 229 and/or mixtures were discarded. Fractions containing the pure components (Compounds 252, 253, 254, and 255) were combined, concentrated to remove organic solvents and lyophilized to afford the TFA salts of the derivatives. After re-analysis by HPLC to confirm purity, samples were submitted for FAB mass spectroscopy. Identification of the compounds was based upon the fragmentation patterns observed in the FAB spectra.

EXAMPLE 6

Table 7 summarizes the preparation and certain physical characteristics of the exemplified compounds. The yield of the product was calculated using the amount of the formula II compound as the limiting reagent. The following terms are found in Table 6 and are defined here. "Method" refers to the method of synthesis as described in Examples 1 and 2, or 3. "Reagent Equivalents" refers to the molar equivalents of the aldehyde and reducing agent relative to the formula II compound. "FAB-MS (M+3H)" refers to Fast atom bombardment-mass spectrometry.

    ______________________________________                                                                     Reagent                                                                        Equivalents                                        Compound                                                                               Yield    Method/    (aldehyde/                                                                              FAB-MS                                    No.     (%)      DMF:MeOH   NaBH3CN) (M+3H)                                    ______________________________________                                          1      28       A/1:1      1.7/6.9  1733*                                      2      45       A/1:1      1.7/6.9  1760                                       3      28       A/1:1      1.8/7.6  1732**                                     4      20       A/0:1      1.8/6.1  1776***                                    5      30       A/0:1      1.8/6.1  1790                                       6      10       A/0:1      1.8/6.1  1768***                                    7      55       A/0:1      1.8/6.1  1740***                                    8      16       A/0:1      1.8/6.1  1826                                       9      32       A/0:1      1.8/6.1  1764***                                    10     6        A/0:1      1.8/6.1  1868                                       11     38       A/0:1      1.8/6.1  1784                                       12     46       A/0:1      1.8/6.1  1940                                       13     32       A/0:1      1.8/6.1  1783**                                     14     5.4      A/1:1      1.9/4.2  1859                                       15     42       A/0:1      1.8/6.1  1763                                       16     39       A/0:1      1.8/6.1  1807**                                     17     41       A/0:1      1.8/6.1  1798                                       18     27       A/0:1      1.8/6.1  1817                                       19     30       A/0:1      1.8/6.1  1739                                       20     5        A/1:1      1.8/1.8  1775*                                      21     11       A/1:1      1.8/1.8  1872*                                      22     8        A/1:1      1.8/1.8  1829**                                     23     ND       A/0:1      1.8/3.6  1888***                                    24     34       A/0:1      1.7/2.5  1685                                       25     31       A/0:1      1.8/1.6  1779                                       26     30       A/0:1      1.7/2.5  1685                                       27     19       A/0:1      1.8/2.5  1734**                                     28     35       A/0:1      1.6/1.6  1735                                       29     39       A/0:1      1.6/1.6  1785**                                     30     29       A/0:1      1.6/1.6  1734**                                     31     11       A/0:1      1.7/2.5  1684**                                     32     28       A/0:1      1.5/1.6  1771**                                     33     ND       A/1:1      1.8/1.8  1789                                       34     ND       A/1:1      1.8/1.8  1836                                       35     ND       A/1:1      1.8/1.8  1785                                       36     ND       A/1:1      1.8/1.8  1835                                       37     31       A/0:1      1.5/1.5  1752***                                    38     16       A/0:1      1.5/1.6  1709                                       39     46       A/0:1      1.5/1.5  1773                                       40     29       A/1:1      1.8/1.8  1846*                                      41     46       A/0:1      1.5/1.5  1729                                       42     53       A/0:1      1.5/1.5  1780                                       43     22       A/0:1      1.1/1.5  1799***                                    44     42       A/0:1      1.5/1.5  1749                                       45     50       A/0:1      1.1/1.5  1841                                       46     38       A/0:1      1.1/1.5  1850                                       47     40       A/0:1      1.5/1.5  1687                                       48     22       A/0:1      1.5/1.5  1728***                                    49     44       A/0:1      1.5/1.5  1776***                                    50     32       A/1:10     2.0/1.5  1774                                       51     32       A/0:1      1.5/1.5  1820                                       52     31       A/0:1      1.5/1.5  1819**                                     53     43       A/0:1      1.5/1.5  1896                                       54     4        A/1:1      1.8/1.8  1789                                       55     21       A/0:1      1.5/1.5  1767                                       56     20       A/0:1      1.1/1.5  1741                                       57     29       A/0:1      1.5/1.5  1820**                                     58     22       A/0:1      1.5/1.5  1727                                       59     ND       A/1:1      1.8/1.8  1803                                       60     33       A/0:1      1.1/1.5  1777**                                     61     24       A/0:1      1.1/1.5  1723                                       62     ND       A/1:1      1.8/1.8  1789**                                     63     ND       A/1:1      1.8/1.8  1789**                                     64     30       A/0:1      1.5/1.5  1805                                       65     24       A/0:1      1.1/1.5  1763                                       66     17       A/0:1      1.1/1.5  1704***                                    67     22       A/0:1      1.1/1.5  1766***                                    68     ND       A/1:1      1.8/1.8  1802                                       69     ND       A/1:1      1.8/1.8  1803                                       70     44       A/0:1      1.1/1.5  1821                                       71     4        A/0:1      1.1/1.5  1796***                                    72     32       A/0:1      1.5/1.5  1750***                                    73     ND       A/1:1      1.8/1.8  1753                                       74     17       A/0:1      1.1/1.5  1815                                       75     23       A/0:1      1.5/1.5  1806***                                    76     16       A/1:1      1.8/1.8  1711                                       77     ND       A/1:1      1.8/1.8  1742                                       78     5        A/1:1      1.8/1.8  1728                                       79     ND       A/1:1      1.8/1.8  1783**                                     80     46       A/0:1      1.5/1.5  1843****                                   81     52       A/0:1      1.5/1.5  1844***                                    82     29       A/0:1      1.5/1.5  1726***                                    83     7        A/0:1      1.5/1.5  1798**                                     84     8        A/0:1      1.5/1.5  1700                                       85     30       A/0:1      1.5/1.5  1775                                       86     45       A/0:1      1.5/1.5  1809                                       87     42       A/0:1      1.1/1.5  1854**                                     88     36       A/0:1      1.1/1.5  1854**                                     89     43       A/1:1      1.8/1.8  1711                                       90     13       A/1:1      1.8/1.8  1787                                       91     20       A/1:10     1.5/1.5  1759**                                     92     23       A/1:10     1.5/1.5  1777                                       93     42       A/0:1      1.5/1.5  1823                                       94     41       A/0:1      1.1/1.5  1854**                                     95     49       A/0:1      1.1/1.5  1789**                                     96     34       A/0:1      1.1/1.5  1832                                       97     42       A/1:10     1.5/1.5  1773**                                     98     31       A/0:1      1/1.5    1805                                       99     ND       A/1:1      1.8/1.8  1770**                                    100     ND       A/1:1      1.8/1.8  1787                                      101     34       A/1:1      1.19/1.8 1761                                      102     41       A/0:1      1.5/1.5  1805                                      103     37       A/0:1      1/1.5    1788***                                   104     34       A/0:1      1.1/1.5  1819**                                    105     ND       A/1:1      1.7/2.0  1838*                                     106     ND       A/1:1      1.7/2.0  1844                                      107     ND       A/1:1      1.1/1.1  1802                                      108     ND       A/0:1      1.8/1.8  1791**                                    109     ND       A/0:1      1.8/1.8  1789                                      110     15       A/0:1      1.1/1.5  1881                                      111     ND       A/1:1      1.8/1.8  1843                                      112     16       A/1:1      1.8/1.8  1764                                      113     45       A/0:1      1.1/1.5  1805**                                    114     52       A/0:1      1.1/1.5  1888**                                    115     39       A/0:1      1.1/1.5  1791                                      116     ND       A/1:1      1.8/2.0  1834                                      117     29       A/0:1      1.5/1.7  1803**                                    118     28       A/0:1      2/1.5    1765**                                    119     41       A/0:1      1/1.5    1843                                      120     38       A/0:1      1.1/1.5  1757                                      121     41       A/0:1      1.1/1.5  1799                                      122     24       A/1:1      1.8/2.6  1863                                      123     55       A/0:1      1.1/1.5  1795**                                    124     17       A/1:10     3/1.5    1781**                                    125     36       A/0:1      1.5/1.8  1841                                      126     26       A/0:1      1.6/1.8  1818                                      127     54       A/0:1      1.1/1.5  1810                                      128     34       A/0:1      1.4/1.8  1831                                      129     ND       A/1:1      1.4/1.8  1780                                      130     4        A/0:1      1.1/1.5  1795**                                    131     42       A/0:1      1.1/1.5  1834**                                    132     49       A/0:1      1.1/1.5  1843                                      133     41       A/0:1      1.1/1.5  1855                                      134     30       A/0:1      1.1/1.5  1801**                                    135     ND       A/1:1      1.8/1.8  1779                                      136     ND       A/1:1      1.8/1.8  1699                                      137     ND       A/1:1      1.8/1.8  1760                                      138     ND       A/1:1      1.8/1.8  1741                                      139     13       A/1:10     2.4/1.5  1749**                                    140     11       A/1:10     2.9/1.5  1750*                                     141     ND       A/1:1      2.3/5.3  1742                                      142     ND       A/1:1      2.5/5.4  1826                                      143     ND       A/1:1      1.8/1.8  1861                                      144     ND       A/1:1      1.5/1.5  1922                                      145     ND       A/1:1      1.1/1.1  1716                                      146     ND       A/1:1      1.35/1.8 1780*                                     147     ND       A/1:1      1.5/1.8  1769                                      148     31       A/1:10     3/1.5    1857                                      149     18       A/0:1      1.1/1.5  1777                                      1S0     22       A/1:1      2/4.8    1803                                      151     ND       A/1:1      1.8/1.8  1760                                      152     ND       A/1:1      1.8/1.8  1826****                                  153     22       A/1:10     2.5/1.6  1782                                      154     ND       A/1:1      1.8/1.8  1780                                      155     13       A/0:1      1.6/1.6  1768                                      156     41       A/1:9      1.2/1.6  1788                                      157     9        A/1:1      2.7/5.4  1810                                      158     ND       A/1:1      1.8/4.1  1854                                      159     13       A/1:9      1/1.6    1807                                      160     13       A/1:9      0.95/1.6 1774                                      161     ND       A/1:1      1.8/1.8  1690                                      162     ND       A/1:1      3.1/6.9  1804                                      163     ND       A/1:1      1.9/5.3  1854                                      164     ND       A/1:1      1.8/1.8  1772                                      165     21       A/1:1      2.0/4.9  1810                                      166     20       A/1:1      2.0/6.2  1870                                      167     23       A/1:1      1.8/4.1  1914                                      168     ND       A/1:1      1.8/1.8  1737                                      169     15       A/1:1      1.8/4.1  1700                                      170     39       A/0:1      1.2/1.1  1728                                      171     32       A/0:1      1.2/1.5  1729**                                    172     11       B/1:1      2.2/4.8  1755**                                    173     51       A/1:9      1.3/1.7  1909                                      174     35       A/1:9      1.5/1.6  1816                                      175     22       B/1:1      1.9/6.2  1742                                      176     21       B/1:1      1.8/6.1  1782                                      177     ND       A/1:1      3.6/1.8  1774                                      178     33       A/1:9      1.4/1.7  1788**                                    179     22       B/1:1      1.8/3.8  1748                                      180     16       A/1:1      1.1/1.3  1591***                                   181     14       A/1:1      1.1/1.3  1617                                      182     17       A/0:1      1.6/6.3  1725                                      183     17       A/0:1      1.6/6.3  1691**                                    184     8        A/0:1      1.6/6.26 1707**                                    185     21       A/1:1      1.1/3.0  1725**                                    186     8        A/1:1      1.1/3.0  1630**                                    187     16       A/1.1      1.6/3.0  2110**                                    188     6        A/1.1      1.5/5.0  2976**                                    189     20       A/1:10     1/1.2    1747**                                    190     9        A/1:10     1.5/1.5  1716                                      191     18       B/1:1      1.8/4.1  1771**                                    192     11       A/0:1      ND/1.8   1738                                      193     24       A/1:10     2.0/1.5  1820**                                    194     27       A/1:10     2.0/1.5  1821                                      195     18       B/1:1      1.6/3.6  1798                                      196     18       B/1:1      1.8/3.9  1754                                      197     35       B/1:1      1.5/3.5  1810                                      198     14       B/1:1      1.5/3.7  1784                                      199     ND       B/1:1      1.5/2.8  1772                                      200     11       B/1:1      1.5/3.7  1828                                      201     14       B/1:1      1.8/6.3  1873**                                    202     7        B/1:1      1.3/5.9  1889**                                    203     15       A/0:1      1.1/1.1  1843                                      204     16       B/1:1      2.0/5.6  1746                                      205     23       B/1:1      1.8/3.7  1732                                      206     11       A/0:1      1.1/1.1  1777                                      207     11       B/1:1      1.6/4.2  1813**                                    208     26       B/1:1      1.9/3.9  1703                                      209     20       A/1:1      1.0/1.6  1774                                      210     35       A/0:1      1.0/1.0  1788                                      211     26       A/0:1      1.3/1.8  1777                                      212     48       A/1:1      1.1/3.1  1849**                                    213     56       A/1:1      1.0/3.6  1849**                                    214     9        B/1:1      1.9/1.9  1732                                      215     35       A/0:1      1.3/1.8  1820***                                   216     31       A/0:1      1.3/1.8  1828***                                   217     12       B/1:1      2.0/2.1  1676                                      218     24       A/1:10     1.2/1.5  1766***                                   219     24       A/1:1      1.4/3.5  1860                                      220     21       A/0:1      1.3/1.8  1785                                      221     42       A/0:1      1.3/1.8  1787                                      222     20       A/0:1      1.1/1.1  1787                                      223     32       A/1:1      2.4/4.5  1817**                                    224     36       A/1:1      1.6/5.6  1773**                                    225     ND       A/0:1      1.1/1.1  1787                                      226     28       A/1:1      1.5/3.0  1766*                                     227     22       A/1:1      1.2/3.7  1777**                                    228     21       A/0:1      1/1.1    1848**                                    229     16       A/0:1      1/1.2    1793                                      230     27       A/0:1      1.3/1.8  1838***                                   231     36       A/0:1      1.3/1.8  1785*                                     232     32       A/1:1      1.8/4.6  1806                                      233     5        A/1:1      1.1/7.3  1878                                      234     7        B/1:1      1.5/3.5  1836*                                     235     15       B/1:1      1.4/4.8  1750                                      236     4        B/1:1      1.4/6.3  1819**                                    237     14       A/0:1      1.1/1.1  1787                                      238     25       B/0:1      1.1/1.1  1771                                      239     22       B/1:1      1.6/1.5  1810                                      240     4.7      A/1:60     1.2/1.1  1810***                                   241     24       B/1:1      1.1/2.5  1779**                                    242     N.D.     A/1:50     1.1/1.2  1787                                      243     20       A/0:1      1.1/1.1  1790                                      244     24       C/0:1      1.1/1.1  1808                                      245     5        C/0:1      1.8/1.8  1864                                      246     3        B/1:1      1.8/6.1  1969.7                                    247     41       A/0:1      1.8/6.1  1957                                      248     ND       E/0:1      3.0/3.0  1925**                                    249     ND       E/0:2      3.0/3.0  2091**                                    250     ND       D/0:3      2.0/3.0  1759**                                    251     ND       E/0:4      3.0/3.0  1925**                                    252     ND       D/0:5      2.0/3.0  1793**                                    253     ND       E/0:6      3.0/3.0  1991**                                    254     ND       E/0:7      3.0/3.0  1994*****                                 255     ND       E/0:8      3.0/3.0  2194*****                                 256     2        A/1:1      1.0/1.8  1805.5                                    257     2        A/1:1      1.0/1.8  1699.4                                    258     2        A/1:1      1.0/1.8  1878.7                                    259     2        A/1:1      1.0/1.8  1734.6**                                  260     16       A/1:9      1.4/1.7  1983**                                    261     4        A/0:1      1.6/1.6  1943*****                                 262     11       A/1:9      1.2/1.6  1982***                                   263     15       A/0:1      1.5/1.5  2015**                                    264     11       A/0:1      1.5/1.5  1974                                      265     18       A/0:1      1.5/1.5  1862                                      266     22       A/0:1      1.5/1.5  2047***                                   267     6        A/0:1      1.5/1.5  2048                                      268     7        A/0:1      1.5/1.5  2046                                      269     18       A/0:1      1.5/1.5  1860*                                     270     19       A/1:10     2/1.5    1954                                      271     14       A/0:1      1.5/1.5  1958                                      272     7        A/0:1      1.5/1.5  1909**                                    273     15       A/0:1      1.5/1.5  1954                                      274     18       A/0:1      1.7/2.5  1775**                                    275     24       A/0:1      1.6/1.6  1875**                                    276     50       A/0:1      1.8/6.1  1885**                                    277     6        A/0:1      1.1/1.5  2088                                      278     20       A/0:1      1.5/1.5  1865**                                    279     4        A/0:1      1.5/1.6  1949**                                    280     19       A/0:1      1.7/2.5  1775**                                    281     41       A/0:1      1.7/2.5  1775**                                    282     22       A/0:1      1.8/6.1  1932*                                     283     5        A/0:1      1.8/6.1  2002                                      284     9        A/0:1      1.8/6.1  1973**                                    285     15       A/0:1      1.6/1.6  1875**                                    286     14       A/0:1      1.8/1.6  1962*                                     287     21       A/0:1      1.5/1.5  1781**                                    288     ND       C          1.8/1.8  2006                                      ______________________________________                                          N.D. = not determined                                                          *M+H                                                                           **M+2H                                                                         ***M+4H                                                                        ****M+6H                                                                       *****M+5H                                                                

EXAMPLE 7

Capsule Formulation

Capsules containing 250 mg of Compound 2 are prepared using the following ingredients:

    ______________________________________                                         Ingredient          Weight                                                     ______________________________________                                         Compound 2 HCl salt     255.4  mg                                              Corn starch flowable powder                                                                            150    mg                                              Corn starch             144.6  mg                                              ______________________________________                                    

Compound 2 (HCl salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 8

Capsule Formulation

Capsules containing 250 mg of Compound 229 are prepared using the following ingredients:

    ______________________________________                                         Ingredient          Weight                                                     ______________________________________                                         Compound 229 HCl salt   255.4  mg                                              Corn starch flowable powder                                                                            150    mg                                              Corn starch             144.6  mg                                              ______________________________________                                    

Compound 2 (HCl salt form, 255.4 mg), corn starch flowable powder (150 mg) and corn starch (144.6 mg) are blended in a suitable mixer until homogenous. The mixture is used to fill a hard gelatin capsule to a net fill weight of 550 mg.

EXAMPLE 9

Suspension Formulation

A sterile insoluble form of compound 2 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the following vehicle:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 10

Suspension Formulation

A sterile insoluble form of compound 229 is milled or screened to a particle size suitable for suspension. This particulate material is suspended in the following vehicle:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 11

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 12

Tablet Formulation

Tablets containing 250 mg of compound 229 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Lecithin          1%                                                           Sodium citrate    2%                                                           Propylparaben     0.015%                                                       Distilled water   q.s. to desired volume                                       ______________________________________                                    

EXAMPLE 13

Tablet Formulation

Tablets containing 250 mg of compound 2 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Compound 2 HCl salt    255.4  mg                                               Microcrystalline cellulose                                                                            101.1  mg                                               Croscarmellose sodium  12.0   mg                                               Providone              12.0   mg                                               Magnesium stearate     3.0    mg                                               Stearic acid           4.0    mg                                               Purified water         0.16   ml                                               ______________________________________                                    

EXAMPLE 14

Tablet Formulation

Tablets containing 250 mg of compound 229 are prepared with the following composition:

    ______________________________________                                         Ingredient        Weight                                                       ______________________________________                                         Compound 229 HCl salt  255.4  mg                                               Microcrystalline cellulose                                                                            101.1  mg                                               Croscarmellose sodium  12.0   mg                                               Providone              12.0   mg                                               Magnesium stearate     3.0    mg                                               Stearic acid           4.0    mg                                               Purified water         0.16   ml                                               ______________________________________                                     

We claim:
 1. A compound of the formula: ##STR9## or a salt thereof.
 2. A pharmaceutical composition comprising 4 4 chlorophenyl!benzyl-A82846B, wherein the 4- 4-chlorophenyl!benzyl is on the amino group of the 4 epi-vancosaminyl sugar of the 4-epi-vancosaminyl-O-glycosyl disaccharide or a salt thereof.
 3. A method of treating a susceptible bacterial infection in an animal which comprises administering to the animal an antibacterially effective amount of a compound of claim 1 or a composition of claim
 2. 4. A method of claim 3 wherein the bacterial infection comprises vancomycin-resistant enteroccoci.
 5. A process for the preparation of a compound of claim 1 which comprisesa) reacting A82846B with 4'-chlorobiphenylcarboxaldehyde in a polar solvent; b) continuing the reaction until formation of a Schriff's base; and c) reducing the Schiff's base by addition of a reducing agent.
 6. A process for the preparation of a compound of claim 1 which comprises reacting A82846B with 4'-chlorobiphenylcarboxaldehyde in a polar solvent and in the presence of a reducing agent, for a time sufficient to produce a compound of claim
 1. 7. A process of claim 6 wherein the reducing agent is sodium cyanoborohydride. 